Exploration of the antibody–drug conjugate clinical landscape

Heather Maecker; Vidya Jonnalagadda; Sunil Bhakta; Vasu Jammalamadaka; Jagath R Junutula

doi:10.1080/19420862.2023.2229101

. 2023 Aug 28;15(1):2229101. doi: 10.1080/19420862.2023.2229101

Exploration of the antibody–drug conjugate clinical landscape

Heather Maecker ^1,^✉,^*,^#, Vidya Jonnalagadda ^1,^*, Sunil Bhakta ¹, Vasu Jammalamadaka ¹, Jagath R Junutula ^1,^✉,^#

PMCID: PMC10464553 PMID: 37639687

ABSTRACT

The antibody–drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, Elahere^TM became the latest ADC to be approved by the US Food and Drug Administration (FDA). To date, over 260 ADCs have been tested in the clinic against various oncology indications. Here, we review the clinical landscape of ADCs that are currently FDA approved (11), agents currently in clinical trials but not yet approved (164), and candidates discontinued following clinical testing (92). These clinically tested ADCs are further analyzed by their targeting tumor antigen(s), linker, payload choices, and highest clinical stage achieved, highlighting limitations associated with the discontinued drug candidates. Lastly, we discuss biologic engineering modifications preclinically demonstrated to improve the therapeutic index that if incorporated may increase the proportion of molecules that successfully transition to regulatory approval.

KEYWORDS: Antibody–drug conjugate, ADC, payload, linker, drug-to-antibody ratio, site-directed conjugation, clinical trials

ADCs as a new class of targeted therapeutics

A new class of precision medicines, antibody–drug conjugates (ADCs), was ushered into oncology clinical practice in 2000 with the US Food and Drug Administration (FDA)’s approval of Mylotarg^TM for the treatment of acute myeloid leukemia (AML). ADC molecules marry the precision of antibody-mediated tumor antigen targeting with potent cytotoxic agents, thereby creating a targeted delivery vehicle for malignant tumors. In this manner, ADCs provide a means to reduce off-tumor toxicities by limiting payload exposure in normal tissues. While most ADC clinical candidates utilize cytotoxic chemotherapeutic payloads, recent ADC candidates have also incorporated targeted small molecules¹ and immunomodulatory agents.² In the 23 years since Mylotarg^TM’s first registration, only 12 of 267 clinically tested ADCs have made it to regulatory approval; 10 occurring in the last 6 years [Figure 1]. Insights into biologic engineering and utilization of less potent linker-payloads (e.g., Enhertu^TM) have re-energized the field and ushered a new wave of drug approvals.

Figure 1. — Timeline of FDA Approvals. To date, 12 ADCs have been granted FDA approval (green boxes). Two candidates, Mylotarg^TM and Blenrep^TM, had their approvals withdrawn (red boxes) due to failure to meet requisite endpoints in post-approval trials. Mylotarg^TM was subsequently re-approved at a lower dose in combination with chemotherapy. Eleven ADC therapeutics are currently FDA approved.

Factors affecting activity of ADCs

ADCs offer several advantages over standard chemotherapies, notably: 1) precision delivery of cytotoxic payloads to cells expressing the selected target antigen, 2) enablement of more potent cytotoxic payload utilization than can be administered systemically, and 3) potential minimization of on target/off tumor toxicity. The promise of ADCs, when successfully designed, is the ability to broaden the therapeutic index over that of systemically administered chemotherapy. By directly delivering the cytotoxic payloads to the tumor tissue, the minimum effective dose (MED) is lowered with corresponding reduction in on target/off tumor adverse events.

Effective analysis of the clinically tested ADC molecules necessitates a fundamental understanding of the factors that modulate their biological activity. The basic cellular processes underlying ADC cytotoxic payload delivery have three key parts. First, the antibody binds to the target antigen on the surface of an antigen-positive cell. Second, the antigen-ADC complex is internalized into the target cell by receptor-mediated endocytosis. Third, the antigen-ADC complex is digested by lysosomal enzymes, releasing the cytotoxic payload that triggers cell death. As illustrated in Figure 2 and discussed below, the effectiveness of these basic cellular processes underlying ADC clinical activity are further modulated by various factors, notably the target antigen, functional attributes of the created antibody, conjugation chemistries, linker attributes, and payload potency and effectiveness for a chosen tumor indication.

Figure 2. — Factors Governing ADC Activity. Grey arrows indicate the path of an ADC into a cell. The antibody binds to the target antigen on the surface of the cell, the antigen-ADC complex is internalized by endocytosis, and the antigen-ADC complex is either recycled back to the cell surface, or transitions to the lysosomal compartment. Lysosomal processing releases the cytotoxic payload (red dots) ultimately triggering cell death. Factors governing this process include the target antigen, the antibody, the conjugation methodology to attach the payload to the biologic, the linker, the payload, and the selected tumor indication.

Target antigen

For an ADC to be effectively internalized within a given cell, a requisite target antigen density needs to exist to trigger efficient receptor-mediated endocytosis. A target antigen density of approximately 10,000 copies/cell or greater has been proposed as a minimum threshold for efficient biologic-mediated ADC internalization.³ Cells with target antigens expressed at lower molecular densities exhibit inefficient ADC internalization with a subsequent reduction in payload delivery. Inefficient ADC internalization can also result in ADC recycling outside of the cell prior to payload processing and release, further reducing the ADC’s cytotoxic effect.⁴ In addition to requisite tumor antigen densities to trigger efficient internalization, the ideal targets chosen for ADC drug development would demonstrate significantly elevated tumor antigen expression over that of normal tissues to minimize the potential for on target/off tumor toxicities. A favorable example of a target that is significantly overexpressed in tumor tissues relative to normal tissues is the HER2/neu antigen that is expressed at lower levels on a subset of normal cells, but expressed at hundreds of thousands to over a million copies on HER2+ cancer cells.⁵ Indeed, ADCs targeting the HER2 antigen have demonstrated robust internalization into HER2-targeted tumor cells with efficient payload delivery^6,7 that has translated to clinical benefit and ultimate drug approval.^8,9 In contrast, ADCs targeting tumor antigens with heterogeneous/low target antigen expression, such as the prolactin receptor with antigen densities of thousands to tens of thousands of molecules/cell,¹⁰ failed to demonstrate clinical responses at the biologic doses tested and were subsequently terminated from future clinical development.¹¹

Antibody

Target epitope choice of a given biologic can greatly alter the effectiveness of the created ADC. Notably, biologics targeting epitopes that promote rapid receptor-mediated internalization show greater activity than biologics targeting non-internalizing epitopes.¹² In addition to epitope choice, biologic affinity can also alter the effectiveness of ADC biologics. Indeed, biologics with lower affinities may demonstrate insufficient binding and/or internalization at lower target antigen densities¹³ and biologics with too high cellular affinities may result in reduced receptor occupancy and/or internalization.¹⁴ Biologic affinity tuning may also help mitigate on target/off tumor toxicities for antigens expressed in normal tissues of concern. Creating biologics with lower cellular affinities could help mitigate toxicity toward target positive normal cells while retaining potency against tumor cells where the given antigen is overexpressed. A preclinical example of this concept is the low affinity EGFR ADC RN765C that demonstrated robust killing of EGFR-positive cell lines/tumor models where EGFR is overexpressed with reduced toxicity against EGFR-positive normal human keratinocytes.¹³

Conjugation

Most ADCs use nonspecific lysine or cysteine residue-directed biologic conjugation. Both conjugation approaches have been found to generate heterogenous ADC products.^15,16 In contrast, site-specific conjugation to native or engineered amino acid residues has been shown to generate more homogenous ADC drug products with improved pharmacokinetic (PK) properties and safety profiles.^17,18

Linker

Linkers can be cleavable or non-cleavable. Cleavable linkers are designed to release the payload inside the targeted cell by protonolysis, thiol reduction, proteolysis, or carbohydrate hydrolysis. In addition to cytosolic payload release, cleavable linkers have also been shown to be cleaved extracellularly due to the presence of cleaving agents in the blood and/or tumor microenvironment (TME). These linkers can be associated with both increased adverse events (due to systemic payload release)¹⁹ and increased efficacy due to noted “bystander effects” (wherein released payload can diffuse across the plasma membrane of a higher tumor antigen expressing cell to adjacent tumor cells with lower antigen expression).²⁰ An ADC can also be created with a non-cleavable linker that only releases payload after proteolysis by lysosomal enzymes. These released payload-adducts are modified such that they do not diffuse across plasma membranes, which limits both their systemic adverse effects but also mitigates the efficacy benefit to neighboring tumor cells due to diminished bystander diffusion.²¹ An excellent example of this concept is the approved clinical ADC, Kadcyla^TM, that employs a non-cleavable linker, limiting its systemic toxicity as well as efficacy to bystander cells expressing lower target antigen densities. Enhertu^TM, in contrast, uses a cleavable linker, and demonstrates bystander killing and greater clinical activity in tumors with lower HER2 target expression.⁹ In a head-to-head clinical trial, Enhertu^TM demonstrated superior clinical activity (mPFS 28.8 months, Enhertu^TM versus 6.8 months, Kadcyla^TM) with comparable incidence of Grade 3 or higher treatment-emergent adverse events (56%, Enhertu^TM versus 52%, Kadcyla^TM) and serious treatment-emergent adverse events (25%, Enhertu^TM versus 22%, Kadcyla^TM).²² In addition to linker choice, choice of payload and presence of tumor drug efflux pumps could have also contributed to these clinical results. Linkers can also vary by their degree of hydrophilicity. Indeed, more hydrophilic linkers have been shown to increase the solubility and favorable PK properties of the ADCs, especially those that use more hydrophobic drug payloads.²³

Payload

The traditional chemotherapeutic ADC payloads fall into three general classes: 1) microtubule inhibitors, 2) DNA-damaging agents, and most recently 3) topoisomerase I inhibitors. The potencies of these payload classes dictate the ADC efficacy and toxicity. Early ADC candidates utilizing low potency payloads of systemically administered chemotherapies (e.g., doxorubicin, IC₅₀ ~ 10^–7 M) were ultimately abandoned due to insufficient clinical activity at administered drug exposures.^24,25 As a result, the ADC field pivoted to the use of increasingly more potent cytotoxic payloads, such as the DNA damaging agents calicheamicin (IC₅₀ ~ 10⁻¹⁰ M) and pyrrolobenzodiazepines (PBDs) (IC₅₀ ~ 10⁻¹² M) and microtubule inhibitors such as monomethyl auristatin E, MMAE (IC₅₀ ~ 10⁻¹⁰ M) for follow-on drug development.²⁶ Utilization of very potent payloads, however, limited the biologic doses that could be administered, often resulting in suboptimal payload delivery to tumors with lower target antigen densities.^27–31 In addition to payload choice, payload ADC effectiveness is also influenced by the 1) number of payload molecules per ADC (drug–antibody ratio, DAR), 2) presence of multi-drug resistance (MDR) efflux pumps in tumors that can expel select payloads, 3) potential bystander functionality of the payload once released, and 4) payload clearance. Bystander functionality is determined by whether the free payload, once released, can diffuse across cellular membranes to trigger a cytotoxic effect. The net charge on the released payload has been found to influence this functionality. For example, released neutral lipophilic MMAE payloads can diffuse across cell membranes to produce a bystander effect, whereas charged MMAF (monomethyl auristatin F) molecules cannot.³²

Payload hydrophobicity has been found to modulate the clearance of the payload. More hydrophobic payloads tend to exhibit more rapid clearance, altering the on-target efficacy and off-target toxicity of a given ADC.²³ In vivo payload metabolism can also modulate ADC safety and efficacy. For example, the SN-38 payload becomes inactivated in the liver with the opening of the lactone ring, dampening its cytotoxic functionality.³³ Finally, clinical success of the ADC depends upon appropriate matching of the payload class to the desired indication as described below.

Indication

The clinical effectiveness of an ADC also depends on the nature of the tumor being targeted. In general, tumors with heterogeneous and/or low target antigen levels are difficult targets for ADCs. Engineering ADCs with bystander activity may in part overcome this challenge as was demonstrated with Enhertu^TM’s recent approval in HER2 low breast cancer.⁹ Tumors with robust expression of multidrug efflux pumps, which expel payloads from tumors, also present challenges for certain classes of ADC payloads. Indeed, ADC resistance in these high efflux tumors can be circumvented with different payload utilization.^34,35

In summary, matching the appropriate tumor antigen to selected ADC linker-payloads for a given cancer indication is critical for development of successful ADC therapeutics.

Analysis of oncology ADCs that have entered clinical trials

Here, we review ADCs registered for at least one human clinical trial for an oncology indication by January 1, 2023, that were included in the Beacon Targeted Therapies Clinical Trials and Pipeline Database (beacon-intelligence.com). We included ADCs that possessed the following two elements: 1) a targeting moiety comprising an antibody, antibody-fusion, or antibody fragment and 2) a payload. The utilized payload is one from either a conventional chemotherapeutic class or a targeted small molecule and/or immune-modulator. Radioisotope ADCs were excluded from this analysis.

In the 26 years since the first ADC clinical trial in 1997, 266 additional ADCs have been tested in over 1200 clinical trials. During this period, 54 ADC programs have been formally discontinued and 38 ADCs have been removed from company pipelines. ADCs covered in this review are classified as 1) Approved (by FDA), 2) Active (not approved by FDA but currently in ≥1 clinical trial), and 3) Discontinued (no longer listed in the company’s clinical pipeline, irrespective of an announcement of discontinuation) [Figure 3]. It should be noted that all Approved ADCs are also currently active in several clinical trials though they are not included in the ‘Active’ category for the purpose of this review (to eliminate double-counting). Additionally, all of the FDA Approved ADCs are approved in other countries in addition to the United States.

Figure 3. — Clinically Tested ADCs. This bar graph captures the 267 ADC that have undergone clinical testing of which: 11 are FDA Approved (green sector), 164 are in Active clinical testing (blue sectors), and 92 have been Discontinued (red sector). Additionally, for the Active ADCs, they have been broken down to highlight their highest development stage (Phase 1-Phase 4, P1-P4). The one candidate in this class listed in Phase 4 (P4), disitamab vedotin, has been approved in China and is not yet approved by the FDA.

Summary of tumor antigens targeted by clinically tested ADCs

The tumor antigen targets and the most advanced stage of clinical testing are illustrated in Figure 4. To date, a total of 106 tumor antigens have been targeted by ADC drug candidates. The 11 approved ADCs target 10 unique cancer antigens: 5 ADCs target hematologic cancer antigens and 6 target solid tumors [Figure 5, Table 1]. Select antigens are the targets of multiple ADCs, including HER2 (41 candidates), Trop-2 (14), CLDN18.2 (11), and EGFR (11). Fewer than 2% of the clinical ADC candidates target more than 1 epitope of selected cancer antigen(s): four bispecific and one biparatopic ADCs are included in this review.

Figure 5. — Approved ADCs Classified by Payload Class and Malignancy Setting. Approved ADC drug name and payload are provided. ADCs are listed from top to bottom based upon the potency of the payload utilized with PBD payloads being the most potent and SN-38 payloads the least potent.

Table 1.

Attributes of FDA Approved ADCs and Approval Indications.

Hematological Malignancies		Solid Tumors
ADC	Indication(s)	ADC	Indication(s)
Adcetris^TM brentuximab vedotin Target: CD30 Conjugation: Nonspecific cysteine Linker: Cleavable, Val-Cit Payload: MMAE DAR ~4	Hodgkin’s Lymphoma after ASCT failure, > 2 L when ASCT is not an option, >1 L sALCL (Accelerated approval based on ORR)	Kadcyla^TM trastuzumab emtansine Target: HER2 Conjugation: Nonspecific lysine Linker: Non-cleavable, SMCC Payload: DM1 DAR ~3.5	HER2+ mBC after treatment with trastuzumab and a taxane, separately or together, HER2+ Early BC as adjuvant treatment in patients with residual disease after neoadjuvant taxane and trastuzumab-based treatment
Besponsa^TM inotuzumab ozogamicin Target: CD22 Conjugation: Nonspecific lysine Linker: Cleavable, AcBut acyl hydrazone-disulfide Payload: Calicheamicin DAR ~2-3	r/r B cell precursor ALL	Enhertu^TM trastuzumab deruxtecan Target: HER2 Conjugation: Specific cysteine Linker: Cleavable, GGFG Payload: DXd DAR ~8	>1 L u/r/m HER2+ BC, HER2-low BC,>1 L HER2+ NSCLC, HER2+ GC/GEJC after trastuzumab-based therapy(Accelerated approval based on ORR, DOR and PFS)
Mylotarg^TM gemtuzumab ozogamicin Target: CD33 Conjugation: Nonspecific lysine Linker: Cleavable, AcBut acyl hydrazone-disulfide Payload: Calicheamicin DAR ~2-3	CD33+ AML in adults, CD33 + r/r AML in patients above 2 y in age	Padcev^TM enfortumab vedotin Target: Nectin-4 Conjugation: Nonspecific cysteine Linker: Cleavable, Val-Cit Payload: MMAE DAR ~4	Locally advanced or metastatic Urothelial Cancer (la/m UC) after treatment with αPD-1/PD-L1 and a platin-containing chemotherapy(Accelerated approval based on OS, PFS, ORR)
Polivy^TM polatuzumab vedotin Target: CD79b Conjugation: Nonspecific cysteine Linker: Cleavable, Val-Cit Payload: MMAE DAR ~3.5	>2 L for DLBCL in combination with bendamustine and a rituximab product (Accelerated approval based on CRR)	Tivdak^TM tisotumab vedotin Target: Tissue Factor Conjugation: Nonspecific cysteine Linker: Cleavable, Val-Cit Payload: MMAE DAR ~4	r/m Cervical Cancer with disease progression on/after chemotherapy(Accelerated approval based on ORR and DOR)
Zynlonta^TM loncastuximab tesirine Target: CD19 Conjugation: Nonspecific cysteine Linker: Cleavable, Val-Ala Payload: PBD DAR ~2.3	>1 L r/r BCL (including DLBCL) (Accelerated approval based on ORR)	Trodelvy^TM sacituzumab govitecan Target: Trop-2 Conjugation: Specific cysteine Linker: Cleavable, CL2A Payload: SN38 DAR ~7.6	>3 L mTNBCla/m, UC after platin-based and αPD-1/PD-L1 therapy(Accelerated approval based on ORR and DOR)
		Elahere^TM mirvetuximab soravtansine Target: Folate Receptor Alpha Conjugation: Nonspecific lysine Linker: Cleavable, Sulfo-SPDB Payload: DM4 DAR ~3.4	2–4 L FRα+ platin-resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer(Accelerated approval based on ORR and DOR)

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Abbreviations: 1 L, first line; 2 L, second line; 3 L, third line; AcBut, 4-(4-acetylphenoxy) butanoic acid; Ala, alanine; ALL, acute lymphoblastic leukemia; ASCT, allogeneic stem cell transplant; BC, breast cancer; BCL, B cell lymphoma; Cit, citrulline; CRR, complete response rate; DAR, drug–antibody ratio; DLBCL, diffuse large B cell lymphoma; DM1, mertansine; DM4, ravtansine; DOR, duration of response; DXd, deruxtecan; FRα, folate receptor alpha; GC, gastric cancer; GEJC, gastroesophageal junction cancer; GGFG, glycine-glycine-phenylalanine-glycine; la/m, locally advanced or metastatic; mBC, metastatic breast cancer; MMAE, monomethyl auristatin E; mTNBC, metastatic triple-negative breast cancer; mUC, urothelial cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PBD, pyrrolobenzodiazepine; PFS, progression free survival; r/m, relapsed/metastatic; r/r, relapsed/refractory; sALCL, systemic anaplastic large cell lymphoma; SMCC, succinimidyl-4-(N-maleimidomethyl cyclohexane)-1-carboxylate; u/r/m, unresectable/recurrent/metastatic; Val, valine.

Summary of linkers utilized by clinically tested ADCs

Linkers fall into two major classes: cleavable and non-cleavable [Figure 6]. Of the clinical ADCs, 54% use cleavable linkers, which represent the most utilized linker class. Ten of 11 clinically approved ADCs use protease-cleavable linkers. Of the clinically tested ADCs, 16% use non-cleavable linkers, including the clinically active ADC Blenrep^TM. Only one approved ADC, Kadcyla^TM, uses a non-cleavable linker. Linker class was not disclosed for 31% of the clinically tested ADCs.

Summary of payloads utilized by clinically tested ADCs

Payloads fall into four major classes: 1) microtubule inhibitors, 2) DNA-damaging agents, 3) topoisomerase I inhibitors, and 4) targeted small molecules (SM) [Figure 7]. Microtubule disrupting agents represent the largest payload class (57%) that have undergone clinical testing. Seven of the 11 approved ADCs use microtubule inhibitor payloads. DNA damaging agents comprise the next largest payload class (17%) of ADCs. In this subgroup, 26 of 45 molecules use highly potent PBD payloads, only one of which was granted FDA approval. Two additional approved ADCs employ the DNA damaging class by utilizing the calicheamicin payload. Topoisomerase I inhibitors are included in 7% of clinically tested ADCs. Of the 11 approved ADCs, two use topoisomerase I inhibitor payloads. In addition to these traditional chemotherapeutic payload classes, roughly 5% of ADCs incorporate targeted small molecules such as Bcl-xL inhibitors, as well as immunomodulatory agents such as TLR and STING agonists. No candidate in this non-chemotherapeutic payload class has yet been granted FDA approval. Payloads for 15% of the clinically tested ADCs are not disclosed.

Figure 7. — Payloads Used in Clinically Tested ADCs. Numbers of ADCs corresponding to the type of payload are shown are shown in the outer ring for the FDA-approved ADCs (green), active ADCs (blue), and discontinued ADCs (red) sectors. Topo-I, Topoisomerase I Inhibitor; SM, targeted small molecules; PBD, pyrrolobenzodiazepine; Cal., calicheamicin.

Summary of conjugation methods utilized by clinically tested ADCs

Of the 267 clinical ADCs, 111 candidates utilized nonspecific amino acid conjugation, 72 candidates utilized site-specific conjugation, and 84 candidates did not disclose the conjugation method for ADC creation. Of the ADC candidates that utilized site-specific ADC conjugation, 2 Approved (Enhertu^TM and Trodelvy^TM), 50 Active, and 26 Discontinued ADCs underwent clinical testing. With the exception of the DAR = 8 ADCs (e.g., Enhertu^TM and Trodelvy^TM) that utilize all natural disulfide bonds for conjugation, the remaining ADCs utilized site-specific conjugation methods that either retain the four inter-chain disulfide bonds or replace these with chemical covalent bonds (e.g., disulfide rebridging).³⁶

Approved ADCs

The FDA has approved 12 ADCs to date [Figure 1, Figure 5, Figure 8, and Table 1], 6 each for hematologic and solid tumor malignancies, respectively [Figure 5, Table 1]. Accelerated conditional approvals were granted to 9 of the 12 approved ADCs. Approvals were withdrawn for 2 (Mylotarg^TM and Blenrep^TM) of the 12 ADCs [Figure 1]. Mylotarg^TM was withdrawn in 2010 due to safety versus clinical benefit concerns but was re-approved in 2017 at a lower dose in combination with chemotherapy.³⁷ Blenrep^TM was withdrawn in 2022 when the confirmatory trial did not meet the requisite post-approval efficacy endpoints.³⁸

Of the 11 currently FDA approved ADCs, 6 utilize microtubule inhibitor payloads. Three approved ADCs use DNA damaging payloads, while 2 carry payloads that inhibit topoisomerase I [Figure 5, Figure 8]. These payloads span a range of potency from the highly potent DNA damaging agent PBD (IC₅₀ ~ pM) to the lower potency topoisomerase I inhibitor SN-38 (IC₅₀ ~ nM).³⁹ Although the sample size is small, approved ADCs used higher potency payloads when targeting hematological malignancies and lower potency payloads were used in ADCs targeting solid tumors. Higher drug exposures required for efficacy in the solid tumor setting may limit utilization of higher potency payloads with reported increased systemic toxicity at the preferred biologic dose.

Active ADCs

Of the 164 Active ADCs, ~7% are in Phase 3 clinical testing. These active late-stage ADCs target the following tumor antigens: BCMA (belantamab mafodotin), CEACAM5 (tusamitamab ravtansine), c-Met (telisotuzumab vedotin), HER2 (trastuzumab duocarmazine and trastuzumab rezetecan), HER3 (patritumab deruxtecan), NaPi-2b (upifitamab rilsodotin), and Trop-2 (datopotamab deruxtecan and SKB264).

Microtubule inhibitor payloads are utilized by most ADCs in the active ADC group (~54%), followed by DNA damaging (10%), and topoisomerase I inhibitor (~9%) payloads. Payloads of ~22% of Active ADCs are undisclosed [Figure 9]. Among microtubule inhibitor ADCs, auristatins are most abundant, followed by maytansines. In the DNA damaging payload class, PBDs comprise ~50% of the clinically active ADCs.

Figure 9. — Active ADCs Classified by Payload Class. Of the active ADCs in clinical testing, the majority utilize microtubule inhibitor payloads, followed by DNA Damaging Agents, Topoisomerase I Inhibitors (Topo-I), and targeted small molecules (SM). ~22% of active ADCs have not disclosed the payload utilized (Undisclosed). PBD, pyrrolobenzodiazepine; Cal., calicheamicin.

Of the cancer antigens targeted by the clinically active ADCs, ~16% target hematologic tumor antigens, ~80% target solid tumor antigens, and ~4% are directed against a cancer antigen that is expressed in both hematologic and solid tumor malignancies. The most frequently targeted tumor antigens in the Active ADC category include HER2 (32 candidates), Trop-2 (11), CLDN18.2 (11), and EGFR (8).

Discontinued ADCs

Discontinuation of ADCs can be ascribed to one or more of the following three reasons: 1) insufficient therapeutic benefit due to intolerable toxicity, 2) therapeutic benefit not superior to current standard of care due to insufficient efficacy, and/or 3) business/commercial considerations. Details of all the discontinued ADCs are shown in Table 2.

Table 2.

Discontinued ADCs by Payload Class and Malignancy Setting.

No.	Target Molecule Conjugation Amino Acid Linker Payload DAR Company Years in Pipeline	Phase Regimen Trial Identifier Status	Indication(s)	Trial Design Results	Ref
	Microtubule Inhibitors – Auristatins – MMAE: Solid Tumors (16)
1	Tyrosine-protein kinase receptor UFO (AXL)enapotamab vedotin; AXL-107-MMAE; HuMax- AXL-ADCNonspecific Cys conj.Cleavable, Val-Cit linker MMAE payloadDAR~4Genmab; Seagen Inc.2016–2020	Phase 1/2 Monotherapy NCT02988817 Completed, minimal efficacy at tolerated doses	OC, Cervical Cancer, NSCLC, Thyroid Cancer, Melanoma, Sarcoma	n = 306, dose escal. 1Q3W (0.3–2.4 mg/kg) and 3Q4W (0.6–1.2 mg/kg); dose exp. at 2.2 mg/kg 1Q3W and 1.0 mg/kg 3Q4W.Safety: Dose escal. DLTs noted in 13.3% pts. Dose exp., 49% pts. had TESAEs, 90% pts. had treatment emergent infusion AEs. 61% pts. had Gr ≥3 TRAEs.Efficacy: Dose exp., 8% ORR.Minimal efficacy at tolerated doses.	²⁵
2	Carbonic anhydrase 9 (CA9) BAY79-4620 Nonspecific Cys conj. Cleavable, Val-Cit linker MMAE payload DAR~ Undisclosed Bayer; MorphoSys 2009–2011	Phase 1 Monotherapy NCT01028755 Completed	Solid Tumors	n = 12, no published results	²⁵
2		Phase 1 Monotherapy NCT01065623 Terminated, safety	Solid Tumors	n = 2, no published results	²⁵
3	Epidermal growth factor receptor (EGFR)losatuxizumab vedotin; ABBV-221Nonspecific Cys conj.Cleavable, Val-Cit linkerMMAE payloadDAR~ 3AbbVie2015–2018	Phase 1 Monotherapy NCT02365662 Terminated, safety	HNSCC, NSCLC, TNBC, CRC, GBM	n = 45, doses 0.3–6.0 mg/kg Q3W.Safety: high incidence of infusion-related AEs (49%; Gr ≥3 in 9%). Several mitigation strategies were explored.Efficacy: 1 PR (2%).Trial halted due to high frequency of infusion-related AEs.	⁴⁰
4	Endothelin receptor type B (EDNRB)DEDN6526A; RG7636Nonspecific Cys conj.Cleavable, Val-Cit linkerMMAE payloadDAR~ UndisclosedRoche-Genentech; Seagen2012–2014	Phase 1MonotherapyNCT01522664Completed, minimal clinical efficacy at tolerated doses	Melanoma	n = 53, dose escal. 0.3–2.8 mg/kg Q3W, RP2D 2.4 mg/kg Q3W.Safety: DLTs included infusion-related reactions, increased ALT/AST, and liver injury. At RP2D, Gr 3+ AEs observed in 38% pts. including neutropenia (25%), ALT increase (7%), infusion reactions and PN (3% each).Efficacy, RP2D: 12.5% PR.Minimal clinical efficacy at tolerated doses.	⁴¹
5	Guanylyl cyclase C (GUCY2C)indusatumab vedotin; 5F9-vcMMAE; MLN0264; TAK-264Nonspecific Cys conj.Cleavable, Val-Cit linkerMMAE payloadDAR ~3.7Takeda; Millennium Pharmaceuticals, Inc.;Seagen Inc.2012–2018Descriptions of Ph. 1 trials (NCT02391038, NCT01577758) are not included.	Phase 2 Monotherapy NCT02202785 Terminated, minimal activity at tolerated doses	PC	n = 43, 1.8 mg/kg Q3W.Safety: 35% pts. experienced ≥3 Gr AEs; 12% had SAEs. Nausea (33%), fatigue (28%), and neutropenia (23%) noted.Efficacy: 3% ORR, 1 PR. Minimal clinical activity noted at tolerated doses.	⁴²
5		Phase 2 Monotherapy NCT02202759 Terminated, minimal efficacy at tolerated doses	Stomach Cancers, GEJC	n = 38, 1.8 mg/kg Q3W.Safety: 37% pts. experienced ≥3 Gr AEs that included anemia, diarrhea, and neutropenia.Efficacy: 6% ORR.Limited efficacy at tolerated doses.	⁴³
6.	Glycoprotein NMB (GPNMB)glembatumumab vedotin; CDX-011; CR011vcMMAENonspecific Cys conj.Cleavable, Val-Cit linkerMMAE payloadDAR~2.7Celldex Therapeutics; Seagen Inc.2008–2018Descriptions of the six Ph2 trials are presented. Descriptions of Ph.1/2 (NCT03326258, NCT02713828, NCT00704158, NCT00412828), Ph. 1 (NCT03473691, ACTRN12617001621303), and Expanded Access (NCT03067935) trials are not included.	Phase 2 Monotherapy NCT02487979 Completed, minimal efficacy noted at doses tested	OS	n = 22, Q3W, dose not specified.Safety: SAEs in 36.4% pts. including rash (13%), anemia (9%), hypokalemia (9%), and febrile neutropenia (4.5%).Efficacy: 4.5% ORR.	²⁵
		Phase 2 Monotherapy NCT02363283 Completed, minimal efficacy noted at doses administered	Uveal Melanoma	n = 35, 1.9 mg/kg Q3W.Safety: The most common Gr 3/4 AE was neutropenia (48%), others occurring in 3–6% of pts. included elevated ALT/AST and leukopenia. One Gr 5 encephalopathy was noted.Efficacy: 6% PR, mDOR 8.6 months, mPFS 3.1 months, mOS 11.9 months. Minimal efficacy noted at doses administered.	⁴⁴
		Phase 2 Combination with varlilumab, nivolumab, pembrolizumab, or CDX-301 (Flt3L) NCT02302339 Terminated, minimal efficacy at doses tested	Melanoma	n = 132; of these 62 pts. given 1.9 mg/kg (reduced to 1.3/1.0 mg/kg in case of DLT).Safety: Gr ≥3 occurred in 37% pts., the most common of these were neutropenia (19%), rash (8%), and neuropathy (7%). A fatal pneumonia was deemed possibly drug related.Efficacy: 11% ORR, mDOR 6.0 months, mPFS 4.4 months, mOS 9.0 months.	⁴⁵
		Phase 2 (METRIC) Combination with capecitabine NCT01997333 Completed, study did not meet primary efficacy PFS endpoint	gpNMB+ TNBC	n = 327, pivotal trial, randomly assigned to 2 arms: ADC (n = 218) vs capecitabine (n = 109).Safety: Gr ≥3 AEs for ADC included neutropenia (28%), rash (12%), leukopenia (9%). SAEs included septic shock that resulted in death (3 pts.).Efficacy: ADC vs capecitabine-mPFS 2.9 vs 2.8 months (HR 1.13), mOS 8.9 vs 8.7 months (HR 1.06),ORR 16% vs 15%.Study did not meet primary endpoint of improved PFS.	⁴⁶
		Phase 2 (EMERGE) Monotherapy vs investigator’s choice (IC) chemotherapy NCT01156753 Completed, ADC arm did not provide improved efficacy over IC comparator arm	BC	n = 124, selected for gpNMB+ in ≥ 5% of epithelial/stromal cells by IHC; randomly assigned 2:1 to ADC (n = 83, 1.9 mg/kg Q3W) or investigator’s choice (IC, n = 41).Safety: ADC vs IC:DLTs 8% vs 5%; 40% of ADC pts. had Gr 3/4 AEs including neutropenia (22%), fatigue (7%), PN (3%).Efficacy: ADC vs IC:ORR 12% vs 12%,PR 6% vs 7%,mOS 7.5 vs 7.4 months.ADC arm did not provide improved efficacy over comparator.	⁴⁷
		Phase 2 Monotherapy, biomarker analysis NCT02487979 Completed, limited efficacy with DLTs noted in 6/22 pts. with one possible fatal TRAE	OS	n = 22 adolescents/YAs, 1.9 mg/kg, Q3W.Safety: DLTs in 6 pts. Gr ≥3 AEs included rash (9.8%) and hypokalemia (6.6%), one possible fatal TRAE, end organ failure.Efficacy: 4.5% PR.Limited efficacy with DLTs noted in 6/22 pts. with one possible fatal TRAE.	⁴⁸
7.	Leucine-rich repeat- containing protein 15 (LRRC15) samrotamab vedotin; ABBV-085 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~2 AbbVie; Seagen Inc. 2015–2019	Phase 1 Monotherapy NCT02565758 Completed, Tolerable safety with evidence of anti-tumor activity	Solid Tumors	n = 85, 0.3–6.0 mg/kg Q2W, dose exp. (n = 45) at 3.6 mg/kg Q2W.Safety, 3.6 mg/kg: Gr ≥3 AEs occurred in 31% of pts. including fatigue (7%), anemia (4%), and neuropathy (4%).Efficacy, 3.6 mg/kg: 20% ORR for osteosarcoma and undifferentiated pleomorphic sarcoma.Tolerable safety with evidence of anti-tumor activity.	⁴⁹
8.	Lymphocyte antigen 6E (LY6E) DLYE5953A; RG7841 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~ Undisclosed Roche-Genentech; Seagen 2014–2017	Phase 1 Monotherapy NCT02092792 Completed, preliminary efficacy noted at doses tested	Solid Tumors including BC and NSCLC	n = 68, 0.2–2.4 mg/kg Q3W; no DLTs, MTD not reached. RP2D 2.4 m/kg Q3W.Safety, RP2D: Gr ≥3 AEs occurred in 25% of pts., including neutropenia (10%) and hypertension (5%).Efficacy, RP2D: 11.5% PR in BC, 22% PR in NSCLC. Preliminary efficacy noted at doses tested.	⁵⁰
9.	Mesothelin (MSLN) DMOT4039A; αMSLN-MMAE; RG7600 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~3.5 Roche-Genentech; Seagen Inc. 2011–2014 Description of Ph. 1 radio-imaging trial (NCT01832116) is not included.	Phase 1 Monotherapy NCT01469793 Completed, limited efficacy at MTD	OC, PC	n = 71 (40 PC, 31 OC), Q3W (n = 54) 0.2–2.8 mg/kg or QW (n = 17) 0.8–1.2 mg/kg. Q3W-MTD and RP2D = 2.4 mg/kg. QW- MTD 1.2 mg/kg and RP2D = 1 mg/kg.Safety, RP2D: Gr ≥3 AEs occurred in 38% of pts., including pyrexia, gastroparesis, hypotension, sinus tachycardia, and infection.Efficacy, RP2D: PC 8% PR, mPFS 1.7 months; OC 30% PR, mPFS 4.9 months.Tolerated but with limited efficacy at MTD.	⁵¹
10.	Mucin-16 (MUC16) sofituzumab vedotin; DMUC5754A; RG7458 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~3.5 Roche-Genentech; Seagen Inc. 2011–2016	Phase 1 Monotherapy NCT01335958 Completed, limited efficacy noted at doses tested	OC, PC	n = 77 (66 PSOC, 11 PC), two dosing regimens: Q3W (n = 54) 0.3–3.2 mg/kg and Q1W (n = 23) 0.8–1.6 mg/kg. RP2D of 2.4 mg/kg Q3W or 1.4 mg/kg QW.Safety, RP2D Q3W: Gr ≥3 AEs included neutropenia (10%), fatigue (10%), and peripheral neuropathy (15%). SAEs included small intestine obstruction, hypocalcemia, and neutropenia. 4 patient deaths were due to AEs: respiratory failure (2), sepsis (1), and acute renal failure (1).Efficacy, RP2D: ~17% ORRLimited efficacy noted at doses tested.	⁵²
11.	Mucin-16 (MUC16) DMUC4064A; D-4064a; RG7882 Specific Cys (THIOMAB^TM) conj. Cleavable Val-Cit linker MMAE payload DAR~2.0 Roche-Genentech; Seagen Inc. 2014–2018	Phase 1 Monotherapy NCT02146313 Completed, evidence of antitumor efficacy at tolerated doses	OC, PC	n = 65, 1.0–5.6 mg/kg. MTD not reached. RP2D of 5.2 mg/kg, Q3W.Safety, RP2D Q3W: Gr ≥3 AEs in 62% pts. including fatigue (15%), keratitis (12%), and blurred vision (4%).Efficacy, RP2D: ~42% ORR, mPFS 5.3 months.Evidence of antitumor efficacy at tolerated doses.	⁵³
12.	Sodium-dependent phosphate transport protein 2B, NaPi-2b (SLC34A2)lifastuzumab vedotin; DNIB0600A; NaPi2b ADC; RG7599Nonspecific Cys conj.Cleavable Val-Cit linkerMMAE payloadDAR~3.5Roche-Genentech; Seagen Inc.2011–2016Descriptions of Ph. 1b trial (NCT01995188) and Ph. 1a trial (NCT01363947) are not included.	Phase 2 Monotherapy vs PLD (PEGylated liposomal doxorubicin)NCT01991210Terminated, primary efficacy PFS endpoint not met	OC	n = 95, randomized 1:1 to ADC (n = 47) vs PLD (n = 48).Safety: ADC Gr ≥3 AEs occurred in 46% pts. including 30% SAEs. Additional AEs included abdominal pain (46%), constipation (24%), diarrhea (35%), neutropenia (28%), and stomatitis (7%).Efficacy: ADC vs PLD – mPFS 5.3 vs 3.1 months, mDOR 5.5 vs 3.9 months,34% ORR (2% CR, 32% PR) vs 15% ORR (2.1% CR and 12.5% PR).Tolerated with objective responses but primary efficacy PFS endpoint not met.	⁵⁴
13.	Choline transporter-like protein 4 (SLC44A4)ASG-5ME; AGS-5; AGS-5MENonspecific Cys conj.Cleavable Val-Cit linkerMMAE payloadDAR~ UndisclosedAgensys, Inc.; Astellas Pharma Inc.; Seagen Inc.2010–2013	Phase 1 Monotherapy NCT01228760 Completed, minimal efficacy at MTD	PC, GC, CRPC	n = 35; PC, n = 20, 0.3–1.5 mg/kg, 3XQW-one week off cycle. MTD 1.2 mg/kg; GC, n = 15, dose exp. at MTD.Safety: Gr ≥3 AEs in 68.6% PC pts. included neutropenia (20%), anemia (8.6%), and pleural effusion (5.7%). Gr ≥3 AEs in 87.6% GC pts. included keratitis (20%), dyspnea and ascites (13% each) and sepsis (6.7%). 1 probable drug-related death, sepsis, in GC patient.Efficacy: 1 PR for PC; 1 PR for GC; DCR of 33% for PC and 47% for GC.n = 46 CRPC, dose esc. (n = 26) 0.3–3.0 mg/kg Q3W, dose exp. (n = 20) at 2.4/2.7 mg/kg Q3W, MTD 2.7 mg/kg Q3W.Safety: Gr ≥3 AEs in 55% dose exp. pts. including 2 deaths attributable to drug (1 multiorgan failure, 1 sepsis).Efficacy: 2 PR.Limited efficacy at MTD.	^55,56
14.	SLIT and NTRK-like protein 6 (SLITRK6) sirtratumab vedotin; ASG-15ME; AGS-15E Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~4 Seagen Inc.; Astellas Pharma Inc. 2013–2018	Phase 1 Monotherapy NCT01963052 Completed	Urothelial Cancer	n = 93, no published results	²⁵
15.	Metalloreductase STEAP-1 (STEAP1)vandortuzumab vedotin; DSTP3086S; RG7450Nonspecific Cys conj.Cleavable Val-Cit linkerMMAE payloadDAR~2.0Roche-Genentech; Seagen Inc.2011–2016	Phase 1 Monotherapy NCT01283373 Completed, minimal efficacy at doses tested	Prostate Cancer	n = 84 (Q3W, n = 77; QW n = 7), 0.3–2.8 mg/kg Q3W, RP2D 2.4 mg/kg Q3W.Safety: Gr ≥3 AEs occurred in 24% of pts., the most common of which were peripheral neuropathy (5%) and ALT increase (5%).Efficacy: >50% PSA reduction in 14% pts.; 4% PR.Minimal efficacy at doses tested.	⁵⁷
16.	Hepatitis A virus cellular receptor 1, TIM-1 (HAVCR1)CDX-014Nonspecific Cys conj.Cleavable Val-Cit linkerMMAE payloadDAR~4.5Celldex Therapeutics2016–2018	Phase 1 Monotherapy NCT02837991 Terminated, limited efficacy at tolerated doses	RCC, Kidney Cancers, OC	n = 16, 0.15 − 2.0 mg/kg Q3W or 1.2 mg/kg Q2W; RP2D 1.8 mg/kg Q3W.Safety: 1 patient death due to multiorgan failure at 2 mg/kg. Other Gr ≥3 included hyperglycemia (19%) and Gr 4 urosepsis in 1 patient.Efficacy: 6% PR, mPFS 2.7 months, OS 12.6 months. Limited efficacy at tolerated doses.	⁵⁸
	Microtubule Inhibitors – Auristatins – MMAE: Hematological Malignancies (6)
17.	B-cell receptor CD22 (CD22) pinatuzumab vedotin; DCDT2980; RG7593 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~3.5 Roche-Genentech 2010–2015 Description of Ph. 1 trial (combination with rituximab; NCT01209130) is not included.	Phase 1/2 (ROMULUS) Combination with obinutuzumab or rituximab compared against polatuzumab vedotin (CD79b) combination arm NCT01691898 Completed, program halted to advance polatuzumab vedotin based on superior clinical activity	DLBCL, FL	n = 231; comparison of rituximab + pinatuzumab vedotin (R-Pina) vs rituximab + polatuzumab vedotin (R-Pola); Arms DLBCL (n = 81; 42 given R-Pina, 39 given R-Pola) and FL (n = 41; 21 given R-Pina, 20 given R-Pola).Safety, R-Pina vs R-Pola: Gr ≥3 AEs in DLBCL 79% vs 77%, in FL 62% vs 50%.Efficacy, R-Pina vs R-Pola: DLBCL- ORR 60% vs 54%; CR 26% vs 21%.FL- ORR 62% vs 70%;CR 5% vs 45%.Pola was selected for advancement based on superior clinical activity.	⁵⁹
18.	Leukocyte antigen CD37 (CD37) AGS67E Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~2.3 Astellas Pharma Inc.; Seagen Inc. 2014–2018	Phase 1 Monotherapy NCT02175433 Completed	Lymphoid Malignancy	n = 71, no published results.	²⁵
18.		Phase 1 Monotherapy NCT02610062 Terminated, business decision	AML	n = 23, no published results.	²⁵
19.	CD48 antigen (CD48) SGN-CD48A Specific Cys conj. Cleavable β-glucuronidase (BG) linker MMAE payload DAR~8 Seagen Inc. 2018–2019	Phase 1 Monotherapy NCT03379584 Terminated, overall benefit/risk profile	MM	n = 14, no published results.	²⁵
20.	B-cell antigen receptor complex-associated protein beta chain (CD79B)iladatuzumab vedotin; DCDS0780A; RG7986Specific engineered Cys (THIOMAB^TM) conj.Cleavable Val-Cit linkerMMAE payloadDAR~2Roche-Genentech; Seagen Inc.2015–2018	Phase 1Monotherapy and Combination with rituximab or obinutuzumabNCT02453087 Completed, did not demonstrate superior efficacy vs Polivy^TM with enhanced ocular toxicity	NHL	n = 60, Monotherapy dose esc. (n = 51) 0.3–4.8 mg/kg Q3W; Combination (n = 9) 3.6 or 4.8 mg/kg with rituximab, 375 mg/m².Safety: Gr ≥3 AEs in (5%) pts. included neutropenia (23%), hypercalcemia (5%), thrombocytopenia (5%), and decreased white blood cell count (5%). 53% of monotherapy and 55% of combination group had ocular toxicity.Efficacy: ADC monotherapy- 47% ORR, 18% PR, 28% CR; ADC + rituximab- 59% ORR, mPFS for all pts. 4.4 months, DLBCL mPFS 3.9 months.Did not demonstrate superior efficacy vs Polivy^TM + rituximab with enhanced ocular toxicity.	⁶⁰
21.	Fc receptor-like protein 5 (FCRL5) DFRF4539A; RG7598 Nonspecific Cys conj. Cleavable Val-Cit linker MMAE payload DAR~ Undisclosed Roche-Genentech; Seagen Inc. 2011–2014	Phase 1 Monotherapy NCT01432353 Completed, minimal efficacy noted at doses tested	MM	n = 39, 0.3–2.4 mg/kg Q3W or 0.8–1.1 mg/kg QW; RP2D 2.4 mg/kg Q3W.Safety, at RP2D: Gr ≥ 3 AEs in 47% pts. including neutropenia (17.6%), thrombocytopenia, acute renal failure, hyponatremia, and nervous system disorders (11.8% each). SAEs in 21% pts. PN in 21% pts.Efficacy, at RP2D: 5% PR, 3% MR.Completed, minimal efficacy noted at doses tested.	⁶¹
22.	SLAM family member 7 (SLAMF7)azintuxizumab vedotin; ABBV-838Nonspecific Cys conj.Cleavable Val-Cit linkerMMAE payloadDAR~ UndisclosedAbbVie2015–2017Description of withdrawn Ph.1 trial (NCT02951117) is not included.	Phase 1Combination with pomalidomide, dexamethasoneNCT02462525Terminated, limited efficacy at tolerated doses	MM	n = 75, dose escal. (n = 32) 0.6–6.0 mg/kg Q3W or (n = 8) 1.5 mg/kg Q1W or (n = 6) 3.0 mg/kg Q2W. Dose exp. (n = 29) at 5.0 mg/kg Q3W.Safety: 73.3% Gr >3 AEs including neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). SAEs in 36.0% pts. PN in 18.7% of pts.Efficacy: 10.7% ORR (2.7% VGPR, 8.0% PR), mDOR 4 months.Limited efficacy at tolerated doses.	⁶²
	Microtubule Inhibitors – Auristatins – MMAF: Solid Tumors (5)
23.	Trophoblast glycoprotein, 5T4 (TPBG) PF-06263507 Nonspecific Cys conj. Non-cleavable mc linker MMAE payload DAR~ 4 Pfizer 2013–2015	Phase 1 Monotherapy NCT01891669 Terminated, severe dose-limiting ocular toxicity without corresponding tumor reduction	Neoplasms, NSCLC, BC, OC	n = 26, 0.5–6.5 mg/kg Q3W, MTD and RP2D 4.34 mg/kg Q3W.Safety: At the RP2D, 16.7% of the pts. had treatment related Gr 3/4 events including ocular toxicity, infection, hypophosphatemia, and embolism. 38.5% of pts. experienced Gr 1/2 ocular toxicity.Efficacy: No ORR.No ORR with severe ocular toxicity.	⁶³
24.	Epidermal growth factor receptor variant III (EGFRvIII)depatuxizumab mafodotin; ABT-414; Depatux-MNonspecific Cys conj.Non-cleavable mc linkerMMAF payloadDAR~ 4AbbVie; Seagen Inc.2013–2018Results of Ph. 2 trials (NCT02343406, NCT02590263), Ph. 1/2 trial (NCT02590263), Ph. 1 trials (NCT01800695, NCT01741727), and one Expanded Access trial (NCT03123952) are not included.	Phase 3b (UNITE) Combination with temozolomide (TMZ) + radiation (RT) vs TMZ + RT assessing differing prophylactic ophthalmologic treatmentsNCT03419403Terminated, ADC was discontinued due to lack of survival benefit	GBM	n = 40Independent Data Monitoring Committee responsible for interim analysis review recommended study termination due to lack of survival benefit.	²⁵
24.		Phase 2/3Combination with temozolomide (TMZ) + radiation (RT) vs TMZ + RTNCT02573324Completed, no difference in OS between ADC and comparator arm	GB, GS	n = 639, double blind randomization 1:1 into 2 Arms, ADC (n = 323; 1.25 mg/kg Q2W) + TMZ + RT vs placebo (n = 316) TMZ + RT; trial amended to Ph. 3 with OS as primary endpoint based on early results of Ph. 2 INTELLANCE-2 trial.Safety: Gr >3 AEs in 80% of ADC group vs 58% placebo. Ocular AEs- 94% vs 36%; thrombocytopenia- 61% vs 36%; gamma-glutamyltransferase increase-10.8% vs 1%.Efficacy: OS 18.9 vs 18.7 months (HR 1.02); mPFS EGFRvIIIm group 8.3 vs 5.9 months; mPFS for pts. without EGFRvIIIm 6.9 vs 7.9 months.ADC provided no OS benefit over placebo arm.	⁶⁴
25.	Ectonucleotide pyrophosphatase/ phosphodiesterase family member 3 (ENPP3)AGS16F; AGS-16C3F; AGS-16M8FNonspecific Cys conj.Non-cleavable mc linkerMMAF payloadDAR~ 4Astellas Pharma Inc.; Seagen Inc.2010–2019Descriptions of Ph. 1 trials (NCT01114230, NCT01672775) are not included.	Phase 2Monotherapy vs axitinibNCT0263912Completed, did not meet primary PFS efficacy endpoint	RC	n = 133, randomized 1:1 ADC at 1.8 mg/kg Q3W vs axitinib.Safety: ADC common AEs included fatigue (53%), nausea (47%), and ocular (44%). ADC Gr >3 AEs included fatigue, dry eye, and thrombocytopenia (3–5%).Efficacy: ADC vs. axitinib – mPFS 2.9 vs. 5.7 months (p = .015), mOS 13.1 vs. 15. 4 months (p = .747).Did not meet primary efficacy endpoint of improved PFS.	⁶⁵
26.	Ephrin type-A receptor 2 (EPHA2) MEDI-547; MI-CP177 Nonspecific Cys conj. Non-cleavable mc linker MMAF payload DAR~ 4 AstraZeneca; Seagen Inc. 2012–2019	Phase 1MonotherapyNCT00796055Terminated, intolerable toxicity with no clinical responses	Solid Tumors	n = 6, 0.08 mg/kg Q3W.Safety: 4/6 (66.7%) pts. experienced SAEs including conjunctival hemorrhage, liver disorder, and hemorrhage deemed to be treatment related.Efficacy: All pts. discontinued treatment due to progressive disease (n = 4) or plan to pursue alternative treatment (n = 2). No clinical responses were observed.Study terminated due to intolerable toxicity with no efficacy benefit.	⁶⁶
27.	CD70 antigen (CD70) vorsetuzumab mafodotin; SGN-75 Nonspecific Cys conj. Non-cleavable mc linker MMAF payload DAR~ 4 Seagen Inc. 2009–2013 Description of Ph. 1 trial (NCT01677390) is not included.	Phase 1 Monotherapy NCT01015911 Completed, minimal efficacy at tolerated doses	RCC, NHL	n = 58 (39 RCC, 19 NHL), 0.3–4.5 mg/kg Q3W or 0.3/0.6 mg/kg Q1W.RCC: MTD 3 mg/kg Q3WNHL: dose esc. terminated due to thrombocytopenic purpura in 2 pts.Safety: Q3W AEs included dry eye (32%), nausea (30%), ocular AEs (57%), and thrombocytopenia (26%). The most common Gr ≥3 AE was thrombocytopenia (19%).Efficacy: Q3W, 1 CR (NHL, MCL), 2 PR (RCC).Minimal activity at tolerated doses.	⁶⁷
	Microtubule Inhibitors – Auristatins – MMAF: Hematological Malignancies (1)
28.	B-lymphocyte antigen CD19 (CD19) denintuzumab mafodotin; SGN-CD19A Nonspecific Cys conj. Non-cleavable mc linker MMAF payload DAR~ Undisclosed Seagen Inc. 2012–2019 Descriptions of Ph. 1 trials (NCT01786135, NCT01786096) are not included; neither has published results.	Phase 2 Combination with rituximab (R) cyclophosphamide (C), doxorubicin (H), vincristine (O), prednisone (P)NCT02855359Terminated, portfolio prioritization	DLBCL, FL, Transformed Lymphoma	n = 24; ADC (3 mg/kg Q6W) + RCHP, n = 11 and ADC (3 mg/kg Q6W) + RCHOP, n = 13.Safety: ADC + RCHP-100% pts. Gr >3 TEAE, 45.5% pts. with SAEs, AE with outcome of death-18.25%; ADC + RCHOP-92.3% pts. TEAE, 23.1% pts. SAEs, AE with outcome of death-7.7%.Efficacy: Efficacy outcomes of mPFS, OS, and ORR not assessed due to lack of study progression to these endpoints.	²⁵
28.		Phase 2 Combination with rituximab, ifosfamide, carboplatin, etoposide (RICE) vs RICENCT02592876Terminated, portfolio prioritization	BCL, DLBCL, FL	n = 81, ADC (3 mg/kg Q3W) + RICE, n = 40 vs RICE, n = 41.Safety: ADC + RICE vs RICE; SAEs 47.5% vs 32.5%, all-cause mortality, 22.5% vs 15%.Efficacy: ADC + RICE vs RICE, 62.5% vs 45% CRR, 80% vs 75% ORR.Insufficient efficacy benefit over comparator arm with enhanced toxicity.	²⁵
	Microtubule Inhibitors – Other Auristatins: Solid Tumors (7)
29.	Tumor antigen AG-7 AbGn-107; Ab1-18Hr1 Nonspecific Cys conj. Cleavable Val-Cit linker MMAD payload DAR~ 2.5 AltruBio Inc. 2017–2021	Phase 1 Monotherapy NCT02908451 Terminated due to COVID	GC, CRC, PC, Biliary Cancer	n = 39, no published results.	²⁵
30.	Urokinase plasminogen activator surface receptor, C4.4a (PLAUR)lupartumab amadotin; BAY1129980Nonspecific Cys conj.Non-cleavable mc-hydrazide linkerAuristatin W analog payloadDAR~ 4Bayer; Seagen Inc.2014–2019	Phase 1 Monotherapy NCT02134197 Terminated, reason not disclosed	Neoplasms	n = 69, no published results.	²⁵
31.	Fibroblast growth factor receptor 2 (FGFR2)aprutumab ixadotin; BAY1187982Nonspecific Lys conj.Non-cleavable Caproyl linkerAuristatin W analog payloadDAR~ 4Bayer2015–2017	Phase 1 Monotherapy NCT02368951 Terminated, intolerable toxicity with no clinical responses	FGFR2+ Solid Tumors	n = 20; 0.1–1.3 mg/kg Q3W, MTD 0.2 mg/kg Q3W.Safety: Gr ≥3 TEAEs included anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia.Efficacy: No clinical responses were observed.Poorly tolerated with MTD reached below the therapeutic threshold estimated for efficacy.	⁶⁸
32.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)XMT-1522; TAK-522Nonspecific Cys conj.Cleavable Fleximer Polymer linkerAuristatin F-HPA payloadDAR~ 12Mersana Therapeutics; Takeda2016–2019	Phase 1 Monotherapy NCT02952729 Completed, minimal clinical activity at the doses tested	HER2+ BC, GC, NSCLC	n = 120 (estimated), prelim results with 19 pts., dose escal. 2.0–21.3 mg/m², no DLTs or SAEs, MTD and RP2D not reached.Safety: TRAEs included elevated liver enzymes, fatigue, nausea, and vomiting (Gr 1 or 2).Efficacy: At doses of 16 and 21.3 mg/m² (6 pts.), 1 PR was observed.Tolerable safety profile but minimal clinical activity at doses tested.	⁶⁹
33.	Sodium-dependent phosphate transport protein 2B, NaPi-2b (SLC34A2)XMT-1592Specific conj. (amino acid not disclosed)Cleavable undisclosed linkerAuristatin F-HPA payloadDAR~ 6Mersana Therapeutics; Synaffix2020–2022	Phase 1/2 Monotherapy NCT04396340 Active, not recruiting	OC, NSCLC	n = 120, no published results	²⁵
34.	Neurogenic locus notch homolog protein 3 (NOTCH3)PF-06650808Nonspecific Cys conj.Cleavable Val-Cit linkerAuristatin (Aur 101) payloadDAR~ UndisclosedPfizer2014–2016	Phase 1 Monotherapy NCT02129205 Terminated, portfolio prioritization	Solid Tumors including BC	n = 40, 0.2–6.4 mg/kg Q3W, MTD 2.4 mg/kg Q3W.Safety: At MTD, 27.3% pts. had DLTs including Gr 3 rash, diarrhea, and thromboembolic event. 54.5% Gr 3 TRAEs included neutropenia, lymphopenia, and AST increase.Efficacy: At MTD, 14.3% pts. had objective responses.Minimal efficacy noted at MTD.	^25,⁷⁰
35.	Tumor-associated calcium signal transducer 2, Trop-2 (TACD2)PF-06664178; RN927CSpecific Glu conj.Cleavable Val-Cit linkerAuristatin (Aur 101) payloadDAR~ 2Pfizer2014–2016	Phase 1 Monotherapy NCT02122146 Terminated, unacceptable toxicity	Solid Tumors	n = 31, 0.15–4.8 mg/kg Q3W.Safety: ≥1 DLTs in 22.5% pts. at doses >3.6 mg/kg. Significant DLTs in skin and mucosa in the dose ranges tested. Gr 3/4 TRAEs noted in 45.5% pts. The most common Gr 4 TRAE was neutropenia and most common Gr 3 TRAE was rash.Efficacy: 0% ORR.Program discontinued due to unacceptable toxicity.	⁷¹
	Microtubule Inhibitors – Maytansine DM1: Solid Tumors (9)
36.	Mucin-1, sialylated carbohydrate tumor antigen CA242 of Mucin-1 (MUC1)cantuzumab mertansine; huC242-DM1; SB- 408075Nonspecific Lys conj.Cleavable SPP linkerDM1 payloadDAR~ 3.5GlaxoSmithKline; ImmunoGen, Inc.1999–2014Description of Ph. 1 trial (HWID128964) is not included.	Phase 1 Monotherapy HWID128999 Completed, tolerated with minimal activity at doses tested	CA242+ Solid Tumors	n = 37; 22–295 mg/m² Q3W, recommended dose 235 mg/m² Q3W.Safety: Reversable elevations of hepatic transaminases were the principal adverse events. Nausea, vomiting, and diarrhea were common but rarely severe at elevated doses.Efficacy: 2 minor regressions noted.Tolerated but with little clinical activity.	⁷²
36.		Phase 1 Monotherapy HWID128907 Completed, no objective responses noted up to and including MTD	CA242+ Solid Tumors	n = 39, 40–138 mg/m² Q1W, MTD: 115 mg/m².Safety: Gr ≥3 AEs at MTD included elevated lipase and alkaline phosphatase (4.3% each).Efficacy: No objective clinical responses (PR or CR) were noted.No objective responses noted up to and including MTD.	⁷³
37.	CD44 antigen, variant 6 (CD44v6)bivatuzumab mertansine; B1W1-1Nonspecific Lys conj.Cleavable SPP linkerDM1 payloadDAR~ UndisclosedBoehringer Ingelheim; ImmunoGen, Inc.2002–2005Descriptions of Ph. 1 trials (NCT02254031, NCT02254018, NCT02254005) are not included.	Phase 1 Monotherapy NCT02254044 Terminated, intolerable, dose limiting skin toxicity	HNSCC	n = 7, dose esc. 20–140 mg/m² Q1W.Safety: Principal AEs- rashes, blisters, desquamation. 3 pts. developed desquamation 5–6 d after 1^st or 2^nd dose; one pt. (140 mg/m²) died of toxic epidermal necrolysis.Efficacy: No objective clinical responses were observed at the doses tested.Program halted due to severe skin toxicity.	^74,75
38.	Neural cell adhesion molecule 1, CD56 (NCAM1)lorvotuzumab mertansine; BB-10901; huN901- DM1; IMGN901Nonspecific Lys conj.Cleavable SPP linkerDM1 payloadDAR~ 3.5ImmunoGen, Inc.2002–2017Descriptions of Ph. 2 trial (NCT02420873), Ph. 1/2 trials (NCT01237678, NCT00065429), and Ph. 1 trials (NCT00991562, NCT00346385, NCT00346255) are not included.	Phase 2 Combination with carboplatin and etoposide (CE) vs CENCT01237678Terminated, intolerable toxicity without efficacy benefit	SCLC	n = 91; ADC arm, n = 44, 90 mg/m², D1/D8 of 21-d cycle + CE vs CE, n = 47.Safety: ADC arm-88% of pts. experienced Gr ≥4 TRAEs including anemia (19%), peripheral sensory neuropathy (18%), neutropenia (17%), and thrombocytopenia (11%). TRAEs resulting in death occurred in 25% of pts. due to lethal infections.Efficacy: ADC arm vs CE-mPFS 6.2 vs 6.7 months (HR = 0.93); mOS estimates 10.1 vs 11 months.Intolerable toxicity without efficacy benefit.	^76,77
39.	CD70 antigen (CD70) AMG 172 Nonspecific Lys conj. Non-cleavable MCC linker DM1 payload DAR~ Undisclosed Amgen; ImmunoGen, Inc. 2012–2016	Phase 1 Monotherapy NCT01497821 Completed, poor tolerability with limited clinical activity	RCC	n = 172; dose esc. 0.15–2.4 mg/kg BIW, MTD 1.6 mg/kg.Safety: TRAEs included thrombocytopenia (59%), anemia (32.4%), hypophosphatemia (29.7%), and AST increase (27%). Drug related DLTs included thrombocytopenia and hepatocellular injury.At 1.6 mg/kg dose, 3/10 pts. had DLTs: Gr 3 liver injury, in 2 pts., Gr 3/4 thrombocytopenia in 2 pts., Gr 3 AST elevations in 2 pts.Efficacy: 5.4% PR.Poor tolerability with limited clinical activity.	⁷⁸
40.	Mast/stem cell growth factor receptor Kit, c-Kit (KIT)LOP628Nonspecific Lys conj.Non-cleavable SMCC linkerDM1 payloadDAR~ UndisclosedImmunoGen, Inc.; Novartis Pharmaceuticals2014–2016	Phase 1 Monotherapy NCT02221505 Terminated, intolerable toxicity	c-KIT+ Solid Tumors	n = 3 GISTs; 0.3 mg/kg (without premedication) 1 patient and 0.15 mg/kg (with premedication) 2 pts.Safety: Hypersensitivity reactions (HSR) noted in all pts. within minutes of infusion of 1^st, 2^nd, or 3^rd dose; pts. were rescued with appropriate treatment; pre-medication controlled HSR, but reactions recurred in subsequent doses and ceased when dosing was discontinued. High serum tryptase noted in all pts.Study was terminated for safety.	⁷⁹
41.	Epidermal growth factor receptor (EGFR)laprituximab emtansine; IMGN289; J2898ANonspecific Lys conj.Non-cleavable SMCC linkerDM1 payloadDAR~ UndisclosedImmunoGen, Inc.2013–2015	Phase 1 Monotherapy NCT01963715 Terminated, reason not disclosed	EGFR+ Solid Tumors	n = 20, no results published	²⁵
42.	Epidermal growth factor receptor variant III (EGFRvIII)AMG 595Nonspecific Lys conj.Non-cleavable SMCC linkerDM1 payloadDAR~ 3.5Amgen; ImmunoGen, Inc.2012–2016	Phase 1 Monotherapy NCT01475006 Completed, poor tolerability and minimal clinical activity at MTD	GBM, AA	n = 32 GBM, 0.5–3.0 mg/kg Q3W, MTD 2.0 mg/kg.Safety: DLT, Gr 4 thrombocytopenia in 31.25% pts., Gr ≥3 TRAEs noted in 53% pts. including thrombocytopenia (44%) and neutropenia, ALT/AST increase, and purpura (3% each).Efficacy: 6% PR.Minimal clinical activity at MTD.	⁸⁰
43.	Cadherin-3, P-Cadherin (CDH3) PCA062 Nonspecific Lys conj. Non-cleavable SMCC linker DM1 payload DAR~ 3.8 ImmunoGen, Inc.; Novartis Pharmaceuticals 2015–2022	Phase 1 Monotherapy NCT02375958 Completed, poor tolerability with minimal clinical activity	TNBC, HNC, Esophageal Cancer	n = 47, 0.4–5.0 mg/kg Q2W, MTD 3.6 mg/kg.Safety: Frequent AEs included elevated AST, anemia, pyrexia, and thrombocytopenia (34% each). 66.0% pts. had SAEs with 55.3% Gr≥3. The most frequently occurring SAE was pyrexia (6.4%). 17% of pts. observed at least one DLT event including thrombocytopenia, AST increase, and anemia.Efficacy: 1 PR (2%).Insufficient efficacy noted at MTD.	⁸¹
44.	Prostate-specific membrane antigen, PSMA (FOLH1)MLN2704Nonspecific Lys conj.Cleavable SPP linkerDM1 payloadDAR~ 3–4Millennium Pharmaceuticals, Inc.2002–2006Description of one Ph.1 trial (NCT00052000) is not included here.	Phase 1/2MonotherapyNCT00070837Completed, dose-limiting neurotoxicity with an absence of objective tumor responses	Prostate Cancer	n = 62, various dose esc. Cohorts: 60–165 mg/m² Q1W (n = 12), 120–330 mg/m² Q2W (n = 15), 330/426 mg/m² Q3W (n = 18), 330 mg/m², D1D15Q6W (n = 17).Safety: PN (71%) – 10% of which were Gr 3/4; nausea (61%), fatigue (60%).Efficacy: Only 8% of pts. experienced ≥ 50% decline in PSA. No objective tumor responses were noted.Neurotoxicity was dose-limiting with no objective tumor responses, attributable in part to labile linker.	⁸²
	Microtubule Inhibitors – Maytansines – DM1: Hematological Malignancies (1)
45.	Tumor necrosis factor receptor superfamily member 17, BCMA (TNFRSF17)AMG 224Nonspecific Lys conj.Non-cleavable MCC linkerDM1 payloadDAR~ UndisclosedAmgen2015–2019	Phase 1 Monotherapy NCT02561962 Completed, evidence of antitumor activity noted at MTD	MM	n = 40; dose escal. 30–250 mg Q3W, n = 29; dose exp. 3 mg/kg Q3W with 2 cohorts: A (prior exposure to anti-CD38 Ab) and B (no prior exposure to anti-CD38 Ab). MTD 190 mg Q3W.Safety: Dose exp., Gr ≥ 3 TEAEs were thrombocytopenia (55%), neutropenia (27%), and anemia (18%). Treatment-emergent ocular AEs (all Gr 1 or 2) occurred in 36%) pts. Drug-related SAEs occurred in 36% pts.Efficacy: 23% ORR (5% sCRs, 5% VG PRs, 13% PRs, mDOR 14.7 months.Evidence of antitumor activity noted at MTD.	⁸³
	Microtubule Inhibitors – Maytansines – DM4: Solid Tumors (7)
46.	Mucin-1 associated sialoglycotope CA6 (MUC1)SAR566658; ACT14884Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ UndisclosedImmunoGen, Inc.; Sanofi2010–2018Description of Ph.1 trial (NCT01156870) is not included.	Phase 2 Monotherapy NCT02984683 Terminated, limited clinical benefit with higher-than- expected rate of ophthalmological toxicity	TNBC	n = 23, 90 mg/m² (n = 11) and 120 mg/m² (n = 12) dosed on day 1 and 8 of a 21-d cycle.Safety: 100% of subjects experienced TRAEs; 90 mg/m²- 9.1% of pts. experienced SAE, 27.3% had TEAEs leading to discontinuation; 120 mg/m²-50% experienced SAE; 25% had TEAEs leading to discontinuation. Corneal toxicities were noted in 3/11 (90 mg/m²) and 5/12 (120 mg/m²) pts.Efficacy: 0% ORR.Limited clinical benefit with higher-than-expected incidence of ophthalmological toxicity.	²⁵
47.	Mucin-1 associated sialoglycotope CA242 (MUC1)cantuzumab ravtansine; IMGN242; HuC242-DM4Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ UndisclosedImmunoGen, Inc.2005–2009Description of Ph.1 trial (NCT00352131) is not included.	Phase 2 Monotherapy NCT00620607 Withdrawn, lack of accrual	Stomach Neoplasms, GC, GEJC	n = 0, study not conducted.	²⁵
48.	Integrin alpha-V, CD51 (ITGAV) IMGN388 Nonspecific Lys conj. Cleavable SPBD linker DM4 payload DAR~ Undisclosed ImmunoGen, Inc. 2008–2011	Phase 1 Monotherapy NCT00721669 Completed	Solid Tumors	n = 60, no published results.	²⁵
49.	Cadherin-6 (CDH6) HKT288; CDH6-ADC Nonspecific Lys conj. Cleavable Sulfo-SPBD linker DM4 payload DAR~ Undisclosed Novartis Pharmaceuticals 2016–2018	Phase 1 Monotherapy NCT02947152 Terminated, unanticipated neurotoxicity with unknown mechanism	RCC, EOC	n = 9 (5 RCC, 4 EOC), starting dose 0.3 mg/kg Q3W.Safety: Common AEs included pyrexia (44.4%), constipation (44.4%), fatigue and vomiting (both 33.3%); Gr 2 neurological AEs in 3 pts. (30%). Unanticipated neurotoxicity with unknown mechanism.Efficacy: No objectives responses observed in doses tested.Limited clinical benefit with unanticipated neurotoxicity with unknown mechanism.	⁸⁴
50.	Teratocarcinoma-derived growth factor 1, Cripto (TDGF1)BIIB015Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ UndisclosedBiogen Idec; ImmunoGen, Inc.2008–2011	Phase 1 Monotherapy NCT00674947 Completed	Solid Tumors	n = 55, no published results.	²⁵
51.	Fibroblast growth factor receptor 3 (FGFR3)LY3076226Nonspecific Lys conj.Cleavable Sulfo-SPBD linkerDM4 payloadDAR~ UndisclosedEli Lilly and Company; ImmunoGen, Inc.2015–2019	Phase 1 Monotherapy NCT02529553 Completed, 0% ORR	Solid Tumors	n = 25; dose escal. n = 22, 0.2–5.0 mg/kg Q3W; dose exp. n = 3, 5.0 mg/kg Q3W.Safety: Most TEAEs were Gr 1/2 and included PN (16%), thrombocytopenia (16%), and diarrhea (32%). Gr 3 AEs in 8% pts. included Gr 3 pulmonary embolism (4%) and Gr 3 thrombocytopenia.Efficacy: 0% ORR.Acceptable safety with no reported clinical activity.	⁸⁵
52.	Lysosome-associate membrane glycoprotein 1 (LAMP-1)SAR428926Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ UndisclosedImmunoGen, Inc.; Sanofi2015–2018	Phase 1 Monotherapy NCT02575781 Completed	Solid Tumors	n = 34, no published results.	²⁵
	Microtubule Inhibitors – Maytansines – DM4: Hematological Malignancies (2)
53.	B-lymphocyte antigen CD19 (CD19) coltuximab ravtansine; SAR3419 Nonspecific Lys conj. Cleavable SPBD linker DM4 payload DAR~ 3.5 ImmunoGen, Inc. 2007–2018 Descriptions of Ph.1 trials (NCT00796731, NCT00549185) are not included.	Phase 2 Monotherapy NCT01472887 Completed, tolerable with evidence of antitumor activity	DLBCL	n = 61, 55 mg/m² 4xQ1W/4xQ2W; 20 pts. eliminated from efficacy analysis (some misclassified).Safety: Gr ≥3 AEs in 38% pts. including hepatotoxicity (3%) and abdominal pain. Ocular AEs observed in 25% of pts.Efficacy: 43.9% ORR, 14.6% CR, mDOR 4.7 months, mPFS 4.4 months, OS 9.2 months.	⁸⁶
		Phase 2 Combination with rituximab NCT01470456 Completed, primary objective of ORR was not met	DLBCL	n = 52, 55 mg/m² + rituximab 4XQ1W/8XQ2W, dose reduced to 40 mg/m² (in case of Gr ≥3 AE.Safety: Gr ≥3 TEAEs in 52% of pts., mostly hematologic AEs including lymphopenia, neutropenia, thrombocytopenia, and anemia. 2 SAEs noted: Gr 1 sinus tachycardia and Gr 4 bronchospasm.Efficacy: 31.1% ORR, 8.9% CR, 22.2% PR, mDOR 8.6 months, mPFS 3.9 months, mOS 9.0 months.Insufficient efficacy: primary objective of ORR, ≥40%, was not met.	⁸⁷
		Phase 2 Monotherapy NCT01440179 Terminated, modest activity compared to competitors	ALL	n = 36, dose esc. (n = 19) 55–90 mg/m²; dose exp. (n = 17) at 70 mg/m².Safety: Gr ≥3 TEAEs in 44% of pts. (55 mg/m²), 63% (70 mg/m²), and 88% of pts. (90 mg/m²) on study. SAEs were reported in 22%, 74%, and 88% of pts. – correlating with dose group. The most common SAEs were bacteremia, pneumonia, and febrile neutropenia.Efficacy (dose exp.): 25.47% ORR (1 CR, 2 CRi, 1 PR), mDOR 1.94 months. Tolerated with low clinical responses vs competitors.	⁸⁸
54.	Myeloid cell surface antigen CD33 (CD33)AVE9633; IMGN-633Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ 3.5ImmunoGen, Inc.; Sanofi2007–2009	Phase 1 Monotherapy NCT00543972 Terminated, minimal clinical activity at MTD	AML	n = 54, 3 dosing regimens: Q3W, D1D8 or D1D4D7 of 28-d cycle, MTD 150 mg/m² for D1D4D7 and 130 mg/m² for D1D8 group.Safety: Main toxicity was allergic reaction during infusion. DLTs of keratitis, liver toxicity for D1D4D7 group. 15% of D1D8 pts. had Gr 3/4 AEs including bronchospasm, keratitis, and liver toxicity. 20% of D1D4D7 pts. had Gr 3/4 events including bronchospasm, erythema, and liver toxicity.Reduction in CD33- blasts noted in D1D8 group.Efficacy: D1D8 − 10% ORR (5% CRi, 5%PR) and D1D4D7 − 0% ORR.Minimal clinical activity at MTD.	⁸⁹
	Microtubule Inhibitors – Other Maytansines: Solid Tumors (2)
55.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)BAT8001Nonspecific Cys conj.Non-cleavable 3AA linkerMaytansine payloadDAR~ 3.5Bio-Thera Solutions Ltd.2017–2021Ph. 1/2 trials (ChiCTR1900022300, NCT04151329) are not included; neither had published results.	Phase 3 Monotherapy vs lapatinib + capecitabine NCT04185649 Unknown, last update 12/4/2019	HER2+ BC	Expected/estimated n = 410, results not published.	²⁵
55.		Phase 1 Monotherapy NCT04182911 Active, not recruiting	HER2+ BC or GC	n = 29, 1.2–6.0 mg/kg Q3W; MTD 3.6 mg/kg.Safety: DLTs of Gr 4 thrombocytopenia and Gr 3 transaminase elevation noted. Gr ≥3 occurred in 48.3% pts., including thrombocytopenia (41.4%), increased AST (13.8%), increased γ‐glutamyl transferase (6.9%), and increased alanine aminotransferase (6.9%) of pts.Efficacy: 41.4% ORR, mPFS 4.3 months.Tolerated with evidence of antitumor efficacy.	⁹⁰
56.	Tumor-associated calcium signal transducer 2, Trop-2(TACD2)BAT8003Specific Engineered Cys conj.Non-cleavable 3AA linkerMaytansine payloadDAR~ 2Bio-Thera Solutions Ltd.2017–2019	Phase 1 Monotherapy NCT03884517 Unknown status; last update March 21, 2019	Solid Tumors	Expected/estimated n = 50, no published results.	²⁵
	Other Microtubule Inhibitor: Solid Tumors (2)
57.	Glypican-3 (GPC3) BMS-986183 Nonspecific Lys conj. Cleavable Val-Cit linker Tubulysin payload DAR~ 3–3.5 Bristol-Myers Squibb 2016–2018	Phase 1/2 Combination with nivolumab (Ph. 2) NCT02828124 Terminated; portfolio prioritization	HCC	n = 25, Combination dose escal. 3–36 mg (n = 10) with nivolumab (Nivo).Safety, Nivo combo dose escal: 40% pts. had SAEs.Efficacy, Nivo combo dose escal.: 0% pts. had objective responses.0% objective responses noted at doses tested.	²⁵
58.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)MEDI4276Specific Engineered Cys conj.Cleavable mc-lysine linkerTubulysin analogue payloadDAR~ 4AstraZeneca2016–2018(Biparatopic antibody)	Phase 1 Monotherapy NCT02576548 Completed, limited efficacy at MTD	HER2+ BC, GC, Stomach Cancers	n = 47, 0.05–0.9 mg/kg Q3W; MTD 0.75 mg/kg Q3W, t½ 0.5–2 d.Safety: Gr ≥3 TRAE occurred in 36.2% pts. The most common Gr ≥3 TRAE included increased AST (21.3%), increased ALT (14.9%), and increased blood bilirubin (6.4%). 10% of pts. had TRAE leading to discontinuation. At the MTD (0.75 mg/kg), MEDI4276 had poor tolerability, as evidenced by the fact that 75.0% of pts. experienced ≥1 serious and/or Gr ≥3 event.Efficacy: BC- 9.4% ORR, 3% CR, 6% PR, mPFS 1.3–15.4 months, mOS 19.1 months.GC -no ORR, mPFS 1.8 months.Limited efficacy at MTD.	⁹¹
	DNA Damaging – PBDs: Solid Tumors (11)
59.	Claudin-6 (CLDN6), Claudin-9 (CLDN9) SC-004 Specific Engineered Cys conj. Cleavable Val-Cit linker PBD Dimer (SG1882) payload DAR~ 2 AbbVie; Stemcentrx 2017–2020	Phase 1/1b Monotherapy or Combination with ABBV-181 (αPD1) NCT03138408 Terminated, low tolerability with limited clinical activity	Epithelial Ovarian Cancer, Endometrial Cancer	n = 24 (11 OC, 13 EC), 0.005–0.3 mg/kg Q3W, MTD 0.2 mg/kg Q3W.Safety: Gr ≥3 TRAEs in 33% pts. including pericardial effusion, pleural effusion, renal failure, and respiratory failure (8% each).Efficacy: 5% PR.Low tolerability with limited clinical activity.	³⁰
60.	Delta-like protein 3 (DLL3) rovalpituzumab tesirine; Rova-T; SC16LD6.5 Nonspecific Cys conj. Cleavable Val-Ala linker PBD Dimer (SG1882) payload DAR~ 2 AbbVie; Stemcentrx; Spirogen 2013–2019 Descriptions of Ph.3 (NCT03334487, study withdrawn), Ph. 2 (NCT03543358, NCT02674568), Ph. 1/2 (NCT03026166, NCT02709889), Ph. 1 (NCT01901653, NCT03086239, NCT03000257, NCT02874664, NCT02819999), and one Expanded Access trial (NCT03503890) are not included here.	Phase 3 (TAHOE) Monotherapy vs topotecan NCT03061812 Completed, Rova-T failed to demonstrate clinical benefit vs topotecan	SCLC	n = 444 (600 were needed for sufficient power), antigen-high (by IHC).ADC dosed at 2 × 0.3 mg/kg Q6W.Safety: ADC vs topotecan-Gr ≥3 AEs in 64% pts. ADC arm vs 88% pts.in Topotecan arm. Serious TRAEs in ADC arm (56%) included malignant neoplasm progression (10%), pneumonia (7%), pleural effusion (6%), and dyspnea (6%).Efficacy: ADC vs topotecan-ORR 15% vs 21%, mDOR 3.5 vs 4.9 months, mOS 6.3 vs 8.6 months (HR 1.46).ADC failed to demonstrate improved clinical benefit vs topotecan.	²⁹
60.		Phase 3 (MERU) Monotherapy vs placebo maintenance after 1 L platin-based therapyNCT03033511Terminated, recommendation of IDMC (toxicity)	SCLC	n = 748; 372 in ADC arm and 376 in placebo arm: ADC dosed at 0.3 mg/kg Q6W, omitting every 3^rd cycle.Safety: Gr ≥3 TEAEs in 59% pts. in ADC arm vs 30% pts. in placebo arm. The most common Gr ≥3 TEAE in ADC arm was thrombocytopenia (9%). TRAEs lead to death in 10% of ADC and placebo arms. ADC discontinuation due to TRAEs in 20% of pts.Efficacy: ADC vs placebo- mOS 8.5 vs 9.8 months; HR = 1.07 favoring placebo arm.ADC showed lack of survival benefit (did not meet primary endpoint).	²⁸
61.	Delta-like protein 3 (DLL3) SC-002 Specific Engineered Cys conj. Cleavable Val-Ala linker PBD Dimer (SG1882) payload DAR~ 2 AbbVie; Stemcentrx 2016–2019	Phase 1 Monotherapy NCT02500914 Terminated, systemic toxicity with insufficient efficacy	SCLC	n = 35, 0.025–0.4 mg/kg Q3W, MTD 0.4 mg/kg Q9WSafety: 66% of pts. experienced ≥ 1 SAE and in at least 37% of the pts. these were considered drug related including one case of lethal pneumonia.Efficacy: 14% PR.Systemic toxicity was postulated to limit the efficacy as was seen with Rova-T.	⁹²
62.	Dipeptidase 3 (DPEP3) tamrintamab pamozirine; SC-003 Specific Engineered Cys conj. Cleavable Val-Ala linker PBD Dimer (SG1882) payload DAR~ 2 AbbVie; Stemcentrx 2015–2018	Phase 1a/b Combination with ABBV-181 (αPD1) NCT02539719 Terminated, lack of requisite safety and efficacy	OC	n = 74 (n = 29 for dose esc; n = 45 dose exp.; n = 3 ABBV-181 combination), MTD 0.3 mg/kg Q3W.Safety: At MTD, 66% of pts. experienced ≥ 1 SAE; 7% experienced Gr 4/5 AEs. 1 death due to kidney injury was deemed treatment related. Common TRAEs included pleural effusion (35%) and peripheral edema (34%).Efficacy: 4% ORR, responses were not durable.Lack of requisite safety and efficacy.	²⁷
63.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)ADCT-502Specific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SG1882) payloadDAR~ 1.7ADC Therapeutics S.A.2017–2018	Phase 1 Monotherapy NCT03125200 Terminated, safety	HER2+ BC, NSCLC, GEC, Bladder Cancer	n = 21, 0.030–0.240 mg/kg Q3W, MTD 0.240 mg/kg.Safety: At doses ≥0.060. mg/kg, 33% pts. had SAEs; 7% experienced Gr 4 /5 events. At doses ≥0.060 mg/kg, 36.8% pts. had treatment emergent SAE including small intestinal obstruction (14%) and peripheral edema, sepsis, pneumonia, pleural effusion (4.8% each).Efficacy: 4.8% PR.Lack of requisite safety and efficacy.	²⁵
64.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)DHES0815A; RG6148Specific Engineered Cys (THIOMAB^TM) conj.Cleavable disulfide linkerPBD-MA payloadDAR~ 2Roche-Genentech2018–2019	Phase 1 Monotherapy NCT03451162 Completed, insufficient efficacy at tolerated doses	BC	n = 14, dose escal. 0.6–6.0 mg/kg Q3W.Safety: 29% pts. discontinued treatment due to AEs. Skin events were reported in 50% of pts. (all doses) and related included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% of pts. with 3 pts. having Gr 3 ocular events. Lung toxicities were reported in 36% of pts., including pneumonitis (14%). Due to these AEs, ADC dose was decreased to 2.4 mg/kg Q3W for all enrolled pts. and accrual was stopped.Efficacy: 7% CR.Insufficient efficacy at tolerated doses.	^93,94
65.	Melanotrasferrin (MELTF) SC-005 Undisclosed conj. method Undisclosed linker PBD payload DAR~ Undisclosed AbbVie; Stemcentrx 2018–2019	Phase 1 Monotherapy NCT03316794 Terminated, sponsor strategic alignment	BC	n = 2, no published results.	²⁵
66.	Prolactin receptor (PRLR) rolinsatamab talirine; ABBV-176 Specific Engineered Cys conj. Cleavable Val-Ala linker PBD Dimer (SFD-1882) payload DAR~ 2 AbbVie; Seagen Inc. 2017–2019	Phase 1 Monotherapy NCT03145909 Terminated, safety	PRLR+ Solid Tumors	n = 19, 0.0027–0.10935 mg/kg Q3W.Safety: Possible cumulative toxicity in the form of effusion and edema.DLTs of thrombocytopenia, neutropenia, and pancytopenia were noted. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity.Efficacy: No ORR.Significant toxicity with absence of objective tumor responses.	¹¹
67.	Prostate-specific membrane antigen, PSMA (FOLH1)ADCT-401; MEDI3726Specific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SFD-1882) payloadDAR~ 1.8ADC Therapeutics S.A.; AstraZeneca2017–2019	Phase 1 Monotherapy NCT02991911 Completed, lack of clinical benefit at tolerated doses	mCRPC	n = 33; 0.015–0.3 mg/kg Q3W, MTD not identified; max. administered dose 0.3 mg/kg.Safety: TRAEs in ~91% pts., primarily skin toxicities and effusions. Gr ≥3 TRAEs in ~46% pts.; 33.3% pts. discontinued due to TRAEs. Gr 3/4 TRAEs included increased gamma-glutamyltransferase (21.2%), thrombocytopenia, capillary leak syndrome (each 9.1%), and increased ALT (6%).Efficacy: 0% ORR, 3% uPR, mPFS 3.6 months, mOS 8.9 months.Lack of efficacy benefit at tolerated doses.	³¹
68.	E3 ubiquitin-protein ligase (RNF43) SC-006 Specific Engineered Cys conj. Cleavable Val-Ala linker PBD (SC-DR003) payload DAR~ 2 Stemcentrx; AbbVie 2017–2019	Phase 1 Combination with ABBV-181 (αPD1) NCT03035279 Terminated, strategic considerations	CRC	n = 29, no results published.	²⁵
69.	Tumor necrosis factor ligand superfamily member 9 (TNFSF9)SC-007Undisclosed conj. methodUndisclosed linkerPBD payloadDAR~ UndisclosedAbbVie; Stemcentrx2017–2018	Phase 1 Monotherapy NCT03253185 Terminated, benefit/risk imbalance	CRC, GC	n = 7, no results published.	^25,95
	DNA Damaging – PBDs: Hematological Malignancies and Solid Tumors (1)
70.	CD70 antigen (CD70) SGN-CD70A Specific Engineered Cys conj. Cleavable Val-Ala linker PBD Dimer (SGD-1882) payload DAR~ 2 Seagen Inc. 2014–2016	Phase 1 Monotherapy NCT02216890 Completed, drug-related thrombocytopenia severity and prevalence cited as reasons for program discontinuation	RCC, MCL, DLBCL, FL	n = 20 NHL; 0.008–0.20 mg/kg Q3W amended to Q6W due to thrombocytopenia, MTD 0.030 mg/kg Q6W.Safety: TEAEs ≥ Gr 3 occurred in 90% pts., including thrombocytopenia (65%), anemia (50%), and fatigue (50%). 55% of pts. experienced drug related SAEs.Efficacy: 20% ORR, 5% CR, 15% PR.Poorly tolerated with insufficient efficacy.	^67,96
	DNA Damaging – PBDs: Hematological Malignancies (7)
71.	B-lymphocyte antigen CD19 (CD19) SGN-CD19B Specific Engineered Cys conj. Cleavable Val-Cit linker PBD Dimer (SG1882) payload DAR~ 2 Seagen Inc. 2015–2018	Phase 1 Monotherapy NCT02702141 Terminated, reason not disclosed	NHL, DLBCL, FL	n = 44, no published results.	²⁵
72.	Neutral amino acid transporter B(0), ASCT2 (SLC1A5)MEDI7247Specific Engineered Cys conj.Cleavable Val-Ala linkerPBD payloadDAR~ 2AstraZeneca2017–2020	Phase 1 Monotherapy NCT03106428 Completed	AML, MM, DLBCL	n = 67; no published results.	²⁵
73.	Tumor necrosis factor receptor superfamily member 17, BCMA (TNFRSF17)MEDI2228Specific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SG3199) payloadDAR~ 2AstraZeneca2018–2021	Phase 1 Monotherapy NCT03489525 Completed	MM	n = 107, no published results.	²⁵
74.	Myeloid cell surface antigen CD33 (CD33)vadastuximab talirine; SGN-CD33ASpecific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SGD-1882) payloadDAR~ 1.9Seagen Inc.2013–2018Ph. 1/2 (NCT02706899, NCT02614560) and Ph. 1 trial (NCT02326584) are not included; neither had published results.	Phase 3 Combination with azacitidine or decitabine vs placebo NCT02785900 Terminated, safety; higher rates of deaths, including fatal infections	AML	n = 240; Trial was halted following a review of unblinded data and consultation with the Independent Data Monitoring Committee. Pts. assigned to the vadastuximab talirine arm had higher rates of death than those in the control arm, including fatal infections.	²⁵
74.		Phase 1 Combination with HMA (hypomethylating agents) azacitidine (AZA) or decitabine (DEC) NCT01902329 Completed, combination with HMA had evidence of antitumor activity at tolerated doses	AML, APML	n = 195, Monotherapy dose escal. (n = 131) 0.005–0.06 mg/kg; expansion dose 0.04 mg/kg selected. Combination (n = 53) AZA for 7 d, n = 23 or DEC for 5 d, n = 27 with ADC dosed (0.01 mg/kg) on last day of AZA/DEC treatment; 28 d treatment cycle.Safety-Monotherapy: Most TEAEs consistent with myelosuppression. 100% of 0.04 mg/kg pts. experienced Gr ≥3 TEAEs that included febrile neutropenia (72%), anemia (42%), and thrombocytopenia (25%).Efficacy–Monotherapy: 0.04 mg/kg monotherapy: CRc (composite remission rate) 28%.Safety-Combination: Gr ≥3 TEAEs reported in 98% of pts. Gr ≥3 TEAEs that included thrombocytopenia (57%), febrile neutropenia (49%), and anemia (45%).Efficacy-Combination: 70% CRc, mOS 11.3 months.Combination with HMA had evidence of antitumor activity at tolerated doses.	^97,98
75.	Interleukin-3 receptor subunit alpha, CD123 (IL3RA)SGN-CD123ASpecific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SGD-1882) payloadDAR~ 2Seagen Inc.2016–2018	Phase 1 Monotherapy NCT02848248 Terminated, reason not disclosed	AML	n = 17, no published results.	²⁵
76.	SLAM family member 6, CD352 (SLAMF6)SGN-CD352ASpecific Engineered Cys conj.Cleavable Val-Ala linkerPBD Dimer (SGD-1882) payloadDAR~ 2Seagen Inc.2016–2018	Phase 1 Monotherapy NCT02954796 Terminated, sponsor portfolio prioritization	MM	n = 27, no published results.	²⁵
77.	C-type lectin domain family 12 member A, CLL-1 (CLEC12A)DCLL9718S; RG6109Specific Engineered Cys (THIOMAB^TM) conj.Undisclosed cleavable linkerPBD payloadDAR~ 2 Roche-Genentech2017–2019	Phase 1 Combination with azacitidine NCT03298516 Completed, limited tolerability and lack of clinical activity	AML	n = 18, dose esc. 0.01–0.16 mg/kg Q3W, MTD not identified.Safety: AEs of Gr ≥3 in 67% pts., including febrile neutropenia (33%) and pneumonia (28%).Efficacy: 0% ORR (CR/PR).Limited tolerability and lack of clinical activity.	⁹⁹
	DNA Damaging – Calicheamicin: Solid Tumors (3)
78.	Ephrin-A4 (EFNA4) PF-06647263 Nonspecific Lys conj. Cleavable AcBut acyl hydrazone-disulfide linker Calicheamicin payload DAR~ 4.6 Pfizer 2014–2019	Phase 1 Monotherapy NCT02078752 Terminated, limited efficacy response at tolerated doses	TNBC, Solid Tumors	n = 60 (48 in dose esc., 12 in dose exp.); dose esc. 0.015–0.134 mg/kg Q3W or 0.01–0.02 mg/kg QW; dose exp. at RP2D of 0.015 mg/kg QW.Safety: TRAEs in >82% pts., AEs of Gr 3/4 in 53.3% including thrombocytopenia (20%). Notable TRAEs are mucosal inflammation (28%), stomatitis (28%), and rash (24%).Efficacy: 10.4% ORR in dose esc; in dose exp. group, 8.3% ORR; no CR.Limited anti-tumor activity at tolerated doses.	¹⁰⁰
79.	Lewis Y antigenCMD-193Nonspecific Lys conj.Cleavable AcBut acyl hydrazone-disulfide linkerCalicheamicin payloadDAR~ UndisclosedWyeth; Pfizer2004–2014	Phase 1 Monotherapy (radiolabeled) NCT00293215 Terminated, abnormal distribution with rapid hepatic uptake and low tumor uptake with rapid clearance from blood	Solid Tumors	n = 9, objective was to determine the biodistribution and PK of⁴⁸ In-CMD-193; CMD-193 demonstrated rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193.Safety: Myelosuppression and prolonged liver uptake which affected liver function were the most significant adverse events. Gr ≥3 AEs included thrombocytopenia (20%) and abnormal liver function (20%).Efficacy: No objective responses were observed.Abnormal drug distribution and low tumor uptake with lack of objective responses.	¹⁰¹
80.	Mucin-1 (MUC-1)CMB-401; hCTMOl-calicheamicinNonspecific Lys conj.Cleavable AcBut acyl hydrazone-disulfide linkerCalicheamicin payloadDAR~ 2–3Pfizer, Celltech Therapeutics1997–2016Description of Ph. 1 trial (PMID 10942064) is not included.	Phase 1 Monotherapy NCT00257881 Terminated, reason not disclosed	Solid Tumors	n = 46 (Japan), no published results.	²⁵
80.		Phase 2 Monotherapy Registry Trial Identifier PMID 12669249 Completed, lack of efficacy noted at tolerated doses	PSEOC	n = 21, pre-dosed with Ab hCTMO1, ADC given at 16 mg/m² Q4W.Safety: 66% of pts. experienced at least 1 Gr ≥3 AE. TRAEs included epistaxis, anemia, AST elevation, and thrombocytopenia. Gr 4 anemia and peritonitis occurred in 1 pt. each.Efficacy: 0% ORR.No anti-tumor activity at tolerated doses.Hypothesized that amide linker may have contributed to the failure to induce PR.	^102,¹⁰³
	Other DNA Damaging: Solid Tumors (2)
81.	Lewis Y antigen SGN-15; BMS-182248; br96-doxPh Nonspecific Cys conj. Cleavable hydrazone linker Doxorubicin payload DAR~ Undisclosed Seagen Inc. 2000–2005 Descriptions of Ph. 2 trials (NCT00031187, NCT00028483, NCT00051584, NCT00086333) are not included; none have published results.	Phase 2 Combination with docetaxel vs docetaxel NCT00051571 Completed, insufficient activity benefit vs comparator arm	NSCLC	n = 62, randomized 2:1 into Arm A (ADC 200 mg/m² Q1W + docetaxel, n = 40) and Arm B (docetaxel alone, n = 19); intrapatient dose escal. up to 350 mg/m² Q1W.Safety: Gr ≥3 AEs in Arm A: increased lipase (25%), nausea/vomiting (18%), asthenia/fatigue (13%); Arm B: respiratory distress (16%), pneumonia (11%), asthenia/fatigue (11%).Efficacy: Arm A vs Arm B, OR 46% vs 37%,mPFS 31.4 vs 25.3 weeks, 1-y survival 29% vs 24%.Insufficient efficacy benefit versus comparator arm.	²⁴
82.	Mesothelin (MSLN) BMS-986148; MDX-1204 Nonspecific Lys conj. Cleavable Val-Cit linker Duocarmycin payload DAR~ 1.4 Bristol-Myers Squibb; Medarex 2009–2018 Description of Ph. 1 trial (NCT02884726) is not included here.	Phase 1/2 Monotherapy and Combination with nivolumab (Nivo) NCT02341625 Terminated, limited clinical activity	MESO, NSCLC, OC, PC, GC	n = 126, Arm A: ADC alone (n = 96; dose esc. 0.1–1.6 mg/kg Q3W/QW) and Arm B: ADC (n = 30, 0.4/0.6/1.2 mg/kg Q3W) + Nivo.Safety: Arm A: 50% pts. treated at 1.6 mg/kg had DLTs, 40% transaminase elevations, 10% Gr 3 pleuritic pain. Combination Arm B: 33% Gr 3/4 AE of ALT/AST increase and pleuritic pain.Efficacy: 2% ORR for ADC monotherapy; 6% ORR in combination group.Limited clinical activity observed alone or in combination with Nivo.	¹⁰⁴
	Other DNA Damaging: Hematological Malignancies and Solid Tumors (1)
83.	CD70 antigen (CD70) MDX-1203; BMS936561; aCD70_MED-A Nonspecific Lys conj. Cleavable Val-Cit linkerMED-A/DNAMGBA toxin (Duocarmycin) payloadDAR~ 1.25Bristol-Myers Squibb; Medarex2009–2018	Phase 1 Monotherapy NCT00944905 Completed, DLTs of Gr 3 hypersensitivity (13%); no efficacy observed at doses tested	RCC, NHL	n = 26, 0.5 − 15 mg/kg Q3W; MTD not defined, RP2D of 8 mg/kg Q3W.Safety: Gr 3 hypersensitivity DLTs (13%) at highest dose; delayed toxicities of facial edema and pleural/pericardial effusion occurred in 38% of pts. at highest dose.Efficacy: 0% OR (PR/CR). No efficacy at doses tested.	¹⁰⁵
	Other DNA Damaging: Hematological Malignancies (2)
84.	Myeloid cell surface antigen CD33 (CD33)IMGN779Nonspecific Lys conj.Cleavable Sulfo-SPDB linkerDGN462 (DNA alkylator) payloadDAR~ 3ImmunoGen, Inc.; Jazz Pharmaceuticals2016–2019	Phase 1 Monotherapy NCT02674763 Completed	AML	n = 62; initial results from 17 pts., dose escal. from 0.02–0.26 mg/kg on days 1 and 15 of a 28-d cycle.Safety: SAEs included Gr 3 febrile neutropenia (29%) and pneumonia (24%). Rash, respiratory failure, and constipation were reported in ≥ 24% of pts. No correlation of frequency and severity of AEs to dose was observed.Efficacy was not reported.	¹⁰⁶
85.	HLA class II histocompatibility antigen gamma chain (CD74)milatuzumab doxorubicin; CD74-DOX; hLL1-DOX; IMMU-110Specific Cys conj.Cleavable Hydrazone linkerDoxorubicin payloadDAR~ 8Immunomedics, Inc.2010–2019	Phase 1/2 Monotherapy NCT01101594 Terminated, lack of efficacy	MM	n = 17, no published results.	²⁵
85.		Phase 1/2 Monotherapy NCT01585688 Terminated, lack of efficacy	NHL, CLL	n = 13, no published results.	²⁵
	Topoisomerase Inhibitors: Solid Tumors (2)
86.	Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)labetuzumab govitecan; hMN14-SN38; IMMU-130Specific Cys conj.Cleavable CL2A linkerSN-38 payloadDAR~ 7.6Immunomedics, Inc.2011–2021Descriptions of Ph. 1/2 trial (NCT01605318) and Ph. 1 trial (NCT01270698) are not included; neither has published results.	Phase 2 Monotherapy NCT01915472 Withdrawn; no participants enrolled	CRC	n = 0, no participants enrolled.	²⁵
86.		Phase 1/2 Monotherapy NCT01270698 Completed, minimal efficacy noted at doses tested	CRC	n = 86 pts., dose exp. 4–10 mg/kg QW or BIW on weeks 1 and 2 of 3-week cycle.Safety: Gr ≥ 3 AEs included neutropenia (16%), leukopenia (11%), and anemia (9%). Toxicity was similar among the 4 cohorts although Gr ≥ 3 AEs were more frequent in the 10 mg/kg QW group (36%).Efficacy: 1 PR (1.16%) from 6 mg/kg BIW treatment group.Minimal efficacy noted at doses tested.	¹⁰⁷
87.	G-protein coupled receptor 20 (GPR20) DS-6157; DS-6157a; GPR20 ADC Specific Cys conj. Cleavable GGFG linker DXd/DX8951 payload DAR~ 8 Daiichi Sankyo, Inc.; Sarah Cannon Research Institute 2020–2021	Phase 1 Monotherapy NCT04276415 Completed, insufficient efficacy noted at tolerated doses	GIST	n = 34, dose esc 1.6–6.4 mg/kg QW3; MTD was 6.4 mg/kg QW3.Safety: Gr ≥3 TRAEs occurred in 41% of pts. including decreased platelets (21%) and anemia (18%). Serious TEAEs (SAEs) occurred in 27% of pts. Related Gr 4 SAEs in 2 pts. included abnormal hepatic function, neutropenia, thrombocytopenia, and leukopenia. There was 1 treatment related death (hepatic failure).Efficacy: One patient had a confirmed PR (~3%), mPFS across all dose levels was 3.6 months.Insufficient efficacy noted at tolerated doses.	¹⁰⁸
	Immunomodulatory Payloads: Solid Tumors (3)
88.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)NJH395Specific Cys conj.Noncleavable linkerUndisclosed TLR7 agonist payloadDAR~ 4Novartis2018–2020	Phase 1 Monotherapy NCT03696771 Completed, insufficient efficacy noted at tolerated doses	Non-breast HER2+ Malignancies	n = 18, dose esc 0.1–1.6 mg/kg.Safety: The most common AE was cytokine release syndrome (55.6% Gr ≥2), pyrexia (44.4%), and AST (33.3%) and ALT (27.8%) increase. The most common Gr ≥3 AEs included lymphopenia (27.8%) and AST increase (11.1%). Five Gr 3 DLTs were reported, 2 AST increase, 1 ALT increase, 1 aseptic meningitis, and 1 meningism.Efficacy: 0% ORR.Insufficient efficacy noted at tolerated doses.	¹⁰⁹
89.	Receptor tyrosine-protein kinase erbB-2, HER2 (ERBB2)SBT6050Undisclosed Cys conj. methodUndisclosed cleavable linkerUndisclosed TLR8 agonist payloadDAR~ 4Silverback Therapeutics2020–2022	Phase 1/2 NCT05091528 Terminated, sponsor portfolio prioritization	HER2+ BC, GC, CRC, NSCLC	n = 2, study not conducted.	²⁵
89.		Phase 1/1bMonotherapy and Combination with pembrolizumab/cemiplimabNCT04460456Active, not recruiting	HER2+ Solid Tumors	n = 58Interim analysis on first 18 pts.; dose escal. 0.15–1.2 mg/kg Q2W.Safety: The most frequent TRAEs (25%) were chills, diarrhea, fatigue, hypotension, injection site reaction, nausea, pyrexia, and vomiting. Gr 3 DLTs were observed at 1.2 mg/kg Q2W. Was concluded that a dose of 0.6 mg/kg Q2W had a tolerable safety profile with evidence of target saturation.Efficacy: 7% PR.Insufficient efficacy noted at tolerated doses.	¹¹⁰
90.	Nectin-4 (NECTIN4) SBT6290 Undisclosed Cys conj. method Undisclosed linker Undisclosed TLR8 agonist payload DAR~ Undisclosed ARS Pharmaceuticals; Silverback Therapeutics2022–2022	Phase 1/2 Monotherapy and Combination with pembrolizumab NCT05234606 Withdrawn, sponsor strategic realignment	UC, TNBC, NSCLC, HNSCC, HR+ HER2- BC	n = 0, study not conducted.	²⁵
	Undisclosed Payloads: Solid Tumors (2)
91.	Leukocyte surface antigen CD47 (CD47) SGN-CD47M Undisclosed conj. method Undisclosed linker Undisclosed payload DAR~ Undisclosed Seagen Inc. 2019–2021	Phase 1 Monotherapy NCT03957096 Terminated, sponsor portfolio prioritization	STS, CRC, HNSCC, NSCLC, BC, OC, Exocrine PC, GC, Melanoma	n = 16, no published results.	²⁵
92.	Alpha-N-acetylneuraminide alpha-2,8- sialtransferase, GD3 (ST8SIA1)PF-06688992; GD3-ADCUndisclosed conj. methodUndisclosed linkerUndisclosed payloadDAR~ UndisclosedPfizer2017–2019	Phase 1 Monotherapy NCT03159117 Completed	Melanoma	n = 7, no published results.	²⁵

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Abbreviations: Ab, antibody; ADC, antibody–drug conjugate; AE, adverse event; Ala, alanine; ALT, alanine transaminase; AML, acute myeloid leukemia; APML, acute promyelocytic leukemia; AST, aspartate transferase; AZA, azacytidine; BIW, twice weekly; Cit, citrulline; CLL, chronic lymphocytic leukemia; conj., conjugation; CRPC, castrate resistant prostate cancer; CR, complete response; CRc, composite complete remission; CRC, colorectal cancer; CRi, complete remission with incomplete blood count recovery; Cys, cysteine; D1D15, day 1 and day 15; DAR, drug–antibody ratio; DCR, disease control rate; DLBCL, diffuse large B cell lymphoma; DLT, dose-limiting toxicity; DM1, mertansine; DM4, ravtansine; EOC, epithelial ovarian cancer; escal., escalation; exp., expansion; FL, follicular lymphoma; Gr, grade; GBM, glioblastoma multiforme; GC, gastric cancer; GEJC, gastroesophageal junction cancer; GIST, gastrointestinal stromal tumors; HNSCC, head and neck squamous cell carcinoma; HR, hazard ratio; HR+, hormone receptor positive; HSR, hypersensitivity reactions; Lys, lysine; mc, maleimidocaproyl; MCL, mantle cell lymphoma; mDOR, medium duration of response; mg/m², milligrams per meter squared; mg/kg, milligrams per kilogram; MM, multiple myeloma; MMAE, monomethyl auristatin E; MR, mixed response; mOS, medium overall survival; mPFS, medium progression free survival; MTD, maximum tolerated dose; NHL, non-Hodgkin lymphoma; Nivo, nivolumab; NSCLC, non-small cell lung cancer; OC, ovarian cancer; ORR, overall response rate; PBD, pyrrolobenzodiazepine; PC, prostate cancer; PK, pharmacokinetic; PLD, pegylated liposomal doxorubicin; PN, peripheral neuropathy; PR, partial response; PSA, prostate-specific antigen; PSOC, platin-sensitive ovarian cancer; pts., patients; QW, weekly; Q2W, every two weeks; Q3W, every three weeks; Q4W, every four weeks; Q6W, every six weeks; Q9W, every nine weeks; RCC, renal cell carcinoma; RP2D, recommended phase 2 dose; RT, radiation; SAE, serious adverse event; sCR, stringent complete response; SMCC, Succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate; SPP, N-succinimidyl 4-(2-pyridyldithio) pentanoate; SPBD, N-succinimidyl 4-(2-pyridyldithio) butanoate; TEAE, treatment emergent adverse event; TESAE, treatment emergent serious adverse event; TMZ, temozolomide; TNBC, triple negative breast cancer; TRAE, treatment related adverse event; uPR, unconfirmed partial response; Val, valine; VGPR, very good partial response; YA, young adults.

Potential factors contributing to insufficient therapeutic benefit due to intolerable toxicity include 1) on target/off tumor toxicity, 2) utilization of very high potency payloads for antigens requiring higher biologic exposures, 3) labile linkers leading to off-tumor release of payload, 4) off-target toxicity, possibly due to pinocytosis of the ADC, and 5) metabolic conversion of the payload to a more toxic metabolite. Approximately 29% of the clinically tested ADCs cited intolerable toxicity as a reason for program termination. Examples of ADCs with intolerable toxicity that could in part be due to on target/off tumor toxicity include bivatuzumab mertansine (CD44v6, expressed in skin keratinocytes) – fatal desquamation,⁷⁴ MEDI-547 (EphA2) – bleeding and coagulation adverse effects (adverse events not typically associated with the MMAE payload),⁶⁶ and PF-06664178 – rash adverse events (Trop-2, expressed on the surface of normal epithelial including skin).⁷¹ For the latter example of PF-06664178, an additional potential contributing factor to the severity of skin toxicity noted is the potent auristatin payload pairing with this Trop-2-targeting ADC. Indeed, the severity of the skin toxicity of PF-06664178 is markedly different from the approved Trop-2-targeting ADC, Trodelvy^TM, which uses a lower potency topoisomerase I inhibitor payload.¹¹¹ Additionally, skin toxicity has also been noted for another auristatin ADC, Padcev^TM, targeting Nectin-4 (also expressed in the skin).¹¹²

Microtubule inhibitor payload ADCs account for 63% of discontinued candidates, followed by DNA damaging (~27%) payloads. Topoisomerase I inhibitors, targeted small molecules, and undisclosed payloads combined comprise 10% of discontinued ADCs [Figure 10]. Utilization of high potency payloads for antigens requiring higher biologic exposures was a likely contributing factor to the intolerable toxicity of several discontinued ADC candidates. The payload choice of biparatopic tetravalent HER2-directed ADC MEDI4276 could have contributed to the intolerable toxicity at doses >0.3 mg/kg.⁹¹ Indeed, the chosen tubulysin analogue payload (IC50 ~ low pM) is in the potency range of PBD payloads.¹¹³ None of the clinically approved ADCs for solid tumors (including 2 ADCs targeting the HER2 antigen) use payloads in this potency range – the most active of which is an ADC employing the less potent payload (Enhertu^TM).²² Safety was noted as the reason for termination HER2 for the PBD-conjugated ADCs ADCT-502²⁵ and DHES0815A.^93,94

Figure 10. — Discontinued ADCs Classified by Payload Class. The major payload classes utilized in the discontinued ADCs are the microtubule inhibitors and DNA Damaging Agents. Topoisomerase I Inhibitors (Topo-1), targeted small molecules (SM), and undisclosed candidates combined make up ~9% of the discontinued ADCs. PBD, pyrrolobenzodiazepine; Cal., calicheamicin.

ADCs targeting six tumor antigens of the approved ADCs (CD19, CD22, CD33, CD79b, HER2, and Trop-2) have also been discontinued, some due to intolerable toxicity. Trodelvy^TM, the approved Trop-2 ADC using the lower potency topoisomerase I payload SN-38 (IC₅₀ ~ nM), requires high biologic exposures to achieve the desired efficacy benefit (10 mg/kg on days 1 and 8 of a 21-day treatment cycle). Two ADCs targeting Trop-2 have been discontinued, most likely due to too potent payload selection pairing with a tumor antigen target requiring higher biologic exposures. PF-06664178, which uses a highly potent auristatin analog payload (IC50~ low pM),¹¹⁴ generated dose-limiting toxicities without any partial and/or complete responses in patients treated with doses up to 4.8 mg/kg every 3 weeks (doses ≥3.6 mg/kg deemed intolerable due to dose-limiting toxicities of rash, mucositis, and neutropenia).⁷¹ No clinical trial data have been published surrounding the highly potent maytansine payload ADC, BAT8003, although dose-limiting toxicities are suspected.

CD79b is targeted by the approved ADC Polivy^TM. A follow-on site-specific CD79b-targeting ADC, iladatuzumab vedotin, was tested in combination with rituximab. Iladatuzumab vedotin was ultimately discontinued because no improvement in the therapeutic index (vs Polivy^TM) was noted due to ocular toxicity at higher doses.⁶⁰

Three ADCs targeting CD33, the target of Mylotarg^TM, were also discontinued. AVE9633 (DM4 payload) showed no clinical activity below toxic doses;⁸⁹ IMGN779 (indolino-benzodiazepine dimer payload) where efficacy was not reported;¹⁰⁶ and vadastuximab talirine (PBD payload) that was discontinued following combination studies with hypomethylating agents citing safety concerns that included fatal infections.⁹⁷ One CD33 targeting ADC with a tubulysin payload, DXC007, is currently in Phase 1 (Registration number CTR20221074), although safety and efficacy data have yet to be released.

Infusion-related adverse events were cited for the discontinuation of LOP628 (c-KIT)⁷⁹ and losatuxizumab vedotin (EGFR).⁴⁰ Additionally, poor tolerability and lack of objective responses of DCLL9718S (CLL-1) at doses tested did not justify its further development.⁹⁹ In some discontinued ADCs, the clinical toxicity profile did not match preclinical observations, such as the CDH6 targeting ADC, HKT288, that showed neurological toxicity in patients not observed in preclinical models.⁸⁴ Similarly, aprutumab ixadotin (FGFR2) had a clinical MTD below the therapeutic threshold estimated preclinically.⁶⁸ These latter two examples highlight the need for better predictive models to guide ADC clinical development.

In addition to intolerable toxicity, insufficient efficacy is also a cause of ADC discontinuation. Factors contributing to insufficient efficacy include 1) low tumor target antigen densities and/or poor internalization properties of discontinued ADCs, 2) insufficient payload potency, 3) heterogenous DAR ADC products resulting in sub-optimal doses of payload, 4) off-tumor payload release and/or incomplete drug release in tumors, 5) rapid clearance of ADC due to poor PK properties, 6) failure to demonstrate efficacy superiority over standard of care, and 7) multidrug resistance mediated through elevated drug efflux transporters in tumors.

Of the discontinued ADC candidates where data is available, insufficient efficacy was a likely contributing factor in ~47% of the cases. Candidates that were reported to demonstrate insufficient efficacy to warrant further clinical testing include, but are not limited to, tamrintamab pamozirine (DPEP3),²⁷ PF-06647263 (EFNA4),¹⁰⁰ and PCA062 (P-Cadherin).⁸¹ It is possible that some of these ADC targets had heterogenous tumor expression and/or insufficient tumor antigen densities to induce efficient ADC internalization.

Utilization of payloads with insufficient potency, contributing to insufficient efficacy, was a possible contributing factor leading to discontinuation of the HER2-targeting immunomodulatory ADCs NJH395 and SBT6050. No objective responses were observed in 18 patients treated with NJH395 (TLR7 agonist payload).¹⁰⁹ Likewise, only one of 14 patients achieved a partial response with SBT6050 (TLR8 agonist payload).¹¹⁰ For these TLR agonist ADCs, it is also possible that the lack of clinical activity is tied to suboptimal activation of an antitumor immune response. The clinical HER2 maytansinoid ADC BAT8001⁹⁰ was discontinued, possibly to advance a less potent topoisomerase I inhibitor payload ADC (BAT8010). This discontinuation/advancement decision is in line with the clinical experience of the two approved HER2 ADCs, Kadcyla^TM and Enhertu^TM, where the ADC employing the lower potency payload (Enhertu^TM) demonstrates greater clinical activity.¹¹⁵

ADCs with heterogenous DAR mixtures resulting in sub-optimal doses of payload was the likely cause of the lower efficacy observed with the nonspecific cysteine conjugate MUC16 ADC, sofituzumab vedotin,⁵² when compared to the specific cysteine (THIOMAB^TM) conjugate ADC, DMUC4064A.⁵³ CMB-401 (MUC1) is an example of an ADC discontinued due to insufficient efficacy that may in part be due to poor linker choice leading to off-tumor payload release.¹⁰² It was suggested that the failure of this calicheamicin ADC to elicit a single partial remission was due to the utilization of the labile amid linker.¹⁰² MEDI4267 is an example of an ADC discontinued due to poor PK properties (and intolerable toxicity). It was noted that this HER2-targeted tubulysin ADC, at MTD, had a very short half-life and high clearance relative to the HER2-targeted ADC, Kadcyla^TM, at its MTD.⁹¹

Seven ADCs were discontinued due to failure to demonstrate superiority over standard chemotherapy comparator arms: rovalpituzumab tesirine (DLL3),^28,29 depatuxizumab mafodotin (EGFRvIII),^64,116,117 AMG 595 (EGFRvIII),⁸⁰ AGS16F (ENPP3),⁶⁵ glembatumumab vedotin (gpNMB),⁴⁶ and lifastuzumab vedotin (NaPi-2b).⁵⁴ Supplementing standard chemotherapy with lorvotuzumab mertansine (CD56) increased incidence of adverse events without enhancing efficacy.^76,118

Clinical information regarding the remaining 22 of the 92 discontinued ADCs remains unpublished (AbGn-107, AGS67E, BAT8003, BIIB015, cantuzumab ravtansine, IMGN388, milatuzumab doxorubicin, laprituximab emtansine, lupartumab amadotin, MEDI2228, MEDI7247, PF-06688992, SAR428926, SBT6290, SC-005, SC-006, SGN-CD19B, SGN-CD48A, SGN-CD123A, SGN-CD352A, sirtratumab vedotin, and XMT-1592). Of these 22, companies cited portfolio prioritization/strategic considerations and lack of accrual for 48% and 2% of discontinuations, respectively, but no reason for discontinuation was given for the remaining 50%.

Implications for future ADC drug design

Development of the next generation of ADCs with a potential to improve their therapeutic index can be broken down into the three main components of the ADC (antibody, linker, payload) and the conjugation technology used to link the antibody to the payload. Also, consideration of the need to match the appropriate payload to a given tumor indication is required, while being mindful of the cancer antigen densities of the tumor targeting biologic.

Improvements to the biologic

Improvements in antibody design include binder selection and engineering to 1) select epitope(s)/affinities that promote maximal internalization, 2) optimize/lower affinity of binders for targets with higher expression on normal tissues of concern, and 3) fine tune the net charge of the ADC to mitigate target-independent toxicity.

Biologics targeting epitopes that promote rapid receptor-mediated internalization show greater activity than biologics targeting non-internalization antigen epitopes.¹² Additionally, biparatopic and bispecific ADC biologics have been reported to improve ADC internalization, increasing the ADC effectiveness in tumors with lower target antigen densities.^119,120 Biparatopic and bispecific ADCs currently in testing include REGN5093-M114 (c-MET, c-MET), zanidatamab zovodotin (HER2, HER2), IMGN151 (FRα FRα), BL-B01D1 (EGFR, HER3), M1231 (EGFR, MUC1), and ORM-5029 (HER2, HER3).

In addition to selecting internalizing epitopes and/or biparatope/bispecific antigen targeting, biologic affinity optimization of ADC biologics would need to be tailored for the antigen(s) of choice. Indeed, biologics with lower affinities may demonstrate insufficient binding and/or internalization at lower target antigen densities¹³ and biologics with too high cellular affinities may result in reduced receptor occupancy and/or internalization.¹⁴ Biologic affinity tuning may also help mitigate on target/off-tumor toxicities for antigens expressed in normal tissues of concern. Affinity de-tuning has been shown to lower target-dependent toxicity in normal tissues while maintaining activity on tumor cells with higher target antigen expression.^13,121

Finally, optimizing the net charge of an ADC has been demonstrated to mitigate target-independent toxicity. An example of this is the reduction in ocular toxicity via introduction of a single Lys to Asp mutation into the biologic of the ADC, AGS-16C3F.¹²² These results suggest that creating a net negative surface charge on the ADC could dampen target-independent toxicity.

Improvements to the linker

Linkers are not mere inert bridges between an antibody and a payload; they influence the stability and PK of a given ADC. Poor performance of some early ADCs, like CMB-401, has been attributed to labile linkers.¹⁰² Improvements in ADC linkers have been shown to decrease systemic payload release and improve PK properties. Along these lines, improvements in linker development could include 1) payload masking linkers, 2) hydrophilic linkers, 3) branched linkers to increase the drug load, 4) tandem cleavage linkers, and 5) dual cleavage-specific linkers.

Modifying the linker to mask the hydrophobic payload can increase the therapeutic index.¹²³ In general, reducing hydrophobicity of an ADC improves PK and therapeutic activity,²³ at least in part due to reduced micropinocytosis-induced off-target toxicity.¹²⁴ Indeed, incorporating hydrophilic macrocycles in the ADC to mask the hydrophobic payloads improved the in vivo activity of Adcetris^TM-like ADCs.¹²⁵

Modifying the linker to increase drug load is another strategy to increase the effectiveness of ADCs that incorporate low potency payloads. One challenge in creating traditional cytotoxic ADCs with higher DAR loads is the increased hydrophobicity of the ADC molecule due to increased numbers of hydrophobic payloads that both increase the probability of aggregation¹²⁶ and hasten clearance of the ADC from the organism.^16,23 Creating polymer linkers, such as Fleximer^TM linkers¹²⁷ or PEG chain additions, either between the antibody and the linker or branching from a location within a traditional linker,²³ can increase the drug load on the ADC molecule without the associated liabilities of biologic degradation and/or clearance. Using such methods, the DAR can be increased without increasing the overall ADC hydrophobicity. Additionally, polypeptides composed of a pseudo-repeating pattern of hydrophilic neutral or negatively charged amino acids (Ala, Gly, Pro, Ser, Thr, Glu; XTEN^TM-peptide based platform) can yield ADCs with DARs as high as 18 without compromising PK.¹²⁸ Increasing linker hydrophilicity can alter the toxicity profile of the ADC by modulating the bystander effect through reduced expulsion of the payload metabolites by the MDR1 pump.¹²⁹ However, this approach may not work for all ADCs.¹³⁰

Lastly, modifying cleavable linkers to minimize systemic release while still maintaining tumor bystander effect could improve the therapeutic index of follow-on ADC molecules. Engineering linkers requiring successive cleavage by enzymes only found inside lysosomes could achieve this property. Such an example was described for a glucuronidase-cleavable linker that when cleaved uncovered a cathepsin cleavage site that enabled payload release – ensuring that both cleavage steps only occurred inside of lysosomes.¹³¹ Such tandem cleavage linkers were found to improve both the stability as well as tolerability of an ADC in a rat toxicity model.¹³¹

Improvements to the payload

Modifications to the payloads that could improve the therapeutic benefit of follow-on ADCs include the creation of 1) prodrug-based payloads to mitigate off-tumor toxicity, 2) creation of hydrophilic cytotoxic payloads, and 3) the creation of bifunctional payloads to increase tumor efficacy. Prodrug payloads exploit the acidic, hypoxic, hyper-sialylated, and protease-rich TME to trigger active payload release in tumors.¹³² Prodrugs can involve masking toxic, hydrophobic payloads such as PBDs by “capping”. The prodrug cap is designed to be cleaved by the TME enzymes, such as beta-glucuronidases, to minimize off-tumor payload release.¹³³ The identification of additional endosomal trafficking modulators and lysosomal pathway regulators for payload release could aid in design of the next generation of prodrug payloads.¹³⁴

The creation of hydrophilic cytotoxic payloads is another potential advancement to develop ADCs with elevated DARs that retain biologic integrity with good PK attributes. An example of this is the hydrophilic payload auristatin β-D-glucuronide MMAU.¹³⁵ This glycoside-payload had the added benefit of being relatively inert in its unconjugated, free form. Lysosomal enzymatic processing to a deglycosylated state activates the payload’s cytotoxic and bystander activity.

The potency of an ADC can also be enhanced with the creation of dual payloads to increase tumor efficacy. Conjugation to two or more different payloads to a given biologic has been shown to have greater antitumor activity over that of a mixture of ADCs carrying the individual payloads. Preclinical studies exploring dual payload ADCs include the two different microtubule inhibitor payloads, MMAE and MMAF,¹³⁶ as well as a microtubule inhibitor payload coupled with a DNA damaging agent such as MMAE and PBD,¹³⁷ or MMAF and PNU-159682.¹³⁸ All of these dual payload ADCs have been shown to increase the antitumor activity over that of a mixture of mono payload ADCs. Additionally, tolerability of these dual payload ADCs in healthy mice was found to be similar to the mono payload ADCs as measured by body weight loss and liver clinical chemistries.¹³⁹

Improvements in payload conjugation

Site-specific attachment of payload yields ADC preparations with controlled and defined DAR. The first method to produce such ADCs via cysteine amino acid engineering gave homogeneous preparations demonstrating superior preclinical PK properties and safety profiles compared to randomly conjugated ADCs.¹⁸ These findings triggered enthusiasm in the field and led to the development of additional methods for site-specific conjugation. To date, site-selective conjugation methods fall into eight categories: cysteine engineering, non-natural amino acid engineering, conjugation to native cysteines, peptide tags, glycan modification, enzymatic modification, disulfide rebridging, and conjugation to native lysines.¹⁴⁰ No method used to date for site-specific conjugation has been shown to have a direct effect on FcRn recycling that can alter ADC PK, efficacy, and safety.

Linker-payload conjugation via non-natural amino acid methods is currently being explored. However, it has been noted that the position of non-natural amino acid conjugation for linker-payload attachment caused a marked effect on tumor killing, although the stability and PK were equivalent.¹⁴¹

Examples of site-specific conjugation using peptide tag technology are the SMARTag^TM and Glutamine Tag. SMARTag^TM achieves site-specific conjugation with the use of an aldehyde tag attaching the linker-payload to formylglycine.¹⁴² Glutamine Tag technology utilizes transglutaminase to attach the linker-payload.¹⁴³ Both technologies were shown to improve PK and efficacy.^142,143

GlycoConnect^TM is an example of a site-specific glycan modification conjugation method. Here, site-specific conjugation is achieved with attachment of the linker-payload following glycan remodeling of the antibody at the Asparagine-297 site.¹⁴⁴ However, since Asparagine-297 glycans are important for antibody Fcγ-receptor effector functions, this method needs to be balanced against the loss of Fc effector function that could otherwise provide an efficacy benefit to the developed ADC.¹⁴⁵

A notable advance in site-specific technology is the AJICAP^TM method that utilizes native lysines for site-specific linker-payload attachment. This method does not require antibody engineering or enzymatic reactions. ADCs so produced were shown to have an improved therapeutic index in preclinical models.¹⁷

Clinically, the site-specific ADC DMUC4064A (MUC16) could be administered at higher biologic doses with higher overall response rates⁵³ than the nonspecific, cysteine-conjugated counterpart sofituzumab vedotin (MUC16).⁵² While promising, site-specific payload conjugation has not always resulted in therapeutic improvement. For example, the site-specific conjugated ADCs iladatuzumab vedotin (CD79b) and SC-002 (DLL3) did not demonstrate an improvement in clinical responses/therapeutic index over that of the nonspecific cysteine-conjugated ADCs Polivy^TM60 and rovalpituzumab tesirine.^29,92

Concluding remarks

Of the 267 ADCs tested for oncology indications, 11 have gained FDA approval; 92 have been discontinued. Analyses of the limitations associated with the discontinued drug candidates can help inform the design and selection of the next series of molecules. Importantly, new biologic engineering modifications have been shown preclinically to improve the therapeutic index. Taking an integrated, multifactorial approach of careful target selection with simultaneous optimization of the antibody, linker, and payload – matched to the indications of interest – will hopefully usher in the next wave of new ADC approvals.

Acknowledgments

The authors wish to thank Beacon Intelligence for providing access to the Beacon Targeted Therapies Clinical Trials and Pipeline Database. The authors would also like to thank Allison Bruce for technical assistance with figure generation.

Funding Statement

No funding was associated with the work of this article.

Abbreviations

ADC: Antibody-Drug Conjugate
ALA: Alanine
AML: Acute Myeloid Leukemia
Asp: Aspartic acid
DAR: Drug-to-Antibody Ratio
FcRn: neonatal Fc receptor
FDA: Food and Drug Administration
Glu: Glutamic acid
Gly: Glycine
IC₅₀: half-maximal inhibitory concentration
Lys: lysine
M: Molar
MDR: Multi-Drug Resistance
MED: minimum effective dose
mg/kg: milligrams per kilogram
MMAE: Monomethyl auristatin E
MMAF: Monomethyl auristatin F
mPFS: Medium Progression Free Survival
MTD: Maximum Tolerated Dose
nM: Nanomolar
PBD: Pyrrolobenzodiazepine
PK: Pharmacokinetic
pM: Picomolar
Pro: Proline
Ser: Serine
SM: Targeted Small Molecules
STING: Stimulator of Interferon Genes
Thr: Threonine
TLR: Toll-Like Receptor
TME: Tumor Microenvironment
US: United States

Disclosure statement

All authors are employees of Aarvik Therapeutics, Inc. and may have stock and/or stock options or interests in Aarvik Therapeutics, Inc.

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PERMALINK

Exploration of the antibody–drug conjugate clinical landscape

Heather Maecker

Vidya Jonnalagadda

Sunil Bhakta

Vasu Jammalamadaka

Jagath R Junutula

ABSTRACT

ADCs as a new class of targeted therapeutics

Figure 1.

Factors affecting activity of ADCs

Figure 2.

Target antigen

Antibody

Conjugation

Linker

Payload

Indication

Analysis of oncology ADCs that have entered clinical trials

Figure 3.

Summary of tumor antigens targeted by clinically tested ADCs

Figure 4.

Figure 5.

Table 1.

Summary of linkers utilized by clinically tested ADCs

Figure 6.

Summary of payloads utilized by clinically tested ADCs

Figure 7.

Summary of conjugation methods utilized by clinically tested ADCs

Approved ADCs

Figure 8.

Active ADCs

Figure 9.

Discontinued ADCs

Table 2.

Figure 10.

Implications for future ADC drug design

Improvements to the biologic

Improvements to the linker

Improvements to the payload

Improvements in payload conjugation

Concluding remarks

Acknowledgments

Funding Statement

Abbreviations

Disclosure statement

References

ACTIONS

PERMALINK

RESOURCES

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