Ultrahigh-DAR antibody–drug conjugates: advancing the next generation of targeted therapy

Abstract

Conventional antibody–drug conjugates (ADCs) are typically limited to drug-to-antibody ratios (DARs) of ≤8 because of restricted conjugation sites and unfavorable physicochemical properties at higher DARs, including increased hydrophobicity, aggregation, and rapid systemic clearance. Consequently, most clinically approved ADCs rely on highly potent cytotoxic payloads (e.g. IC₅₀ < 1 nM), which can result in significant off-target toxicities. This mini-review summarizes recent advances in next-generation ultrahigh-DAR antibody therapeutics, with a particular focus on two emerging platforms: antibody polymer conjugates (APCs) and antibody–nanoparticle conjugates (ANCs). We discuss their design principles, structural features, and strategies for achieving high payload loading while preserving antigen recognition and favorable pharmacokinetic properties. Recent advances in APCs and ANCs demonstrate that polymer and nanomaterial engineering can overcome the conventional DAR limitations of ADCs, enabling substantially greater payload loading per targeting antibody without compromising targeting performance. These ultrahigh-DAR platforms also expand the range of deliverable payloads, facilitating the development of therapeutics with diverse mechanisms of action beyond traditional ultrapotent cytotoxic agents. Ultrahigh-DAR antibody therapeutics represent a promising next generation of targeted drug delivery systems. By integrating advances in polymer and nanomaterial engineering, APCs and ANCs have the potential to broaden the therapeutic landscape of antibody-based medicines and enable safer, more effective targeted therapies across a wide range of diseases.

Statement of Significance This mini-review highlights emerging antibody conjugates with ultrahigh DARs, focusing on polymer- and nanoparticle-based platforms. By expanding payload capacity, these strategies enable alternative, more selective, and less toxic drugs and provide key design principles for overcoming DAR limitations in next-generation antibody therapeutics.

Introduction

Monoclonal antibodies (mAbs) play a central role in targeted therapeutics due to their antigen-binding specificity, long circulation half-life, and favorable safety profiles [1, 2]. They enabled the development of antibody–drug conjugates (ADCs) (Fig. 1a), which selectively deliver drugs to targeted cells while sparing neighboring healthy tissue [3]. ADCs are now clinically approved for multiple oncology indications, establishing antibody-guided drug delivery as a validated therapeutic strategy.

Figure 1.

ADC design principles and the impact of DAR; (a) schematic of a conventional ADC, composed of a monoclonal antibody, a chemical linker, and a cytotoxic payload; adapted from Fu et al. [3] under a Creative Commons CC BY license; (b) distribution of IC₅₀ values for representative cytotoxic agents; only highly potent compounds (IC₅₀ < 1 nM, shaded region) are suitable as payloads in clinically approved ADCs; reproduced with permission from Nakada et al. [5]; Copyright © 2019 The Pharmaceutical Society of Japan; (c) top: in vitro cytotoxicity of ADCs in Karpas-299 cells, shown as cell viability versus ADC concentration; E2, E4, and E8 denote ADCs with DARs of 2, 4, and 8 conjugated to cAC10, respectively; middle: in vivo pharmacokinetic profiles as a function of DAR; bottom: relationship between single-dose efficacy and DAR; black and white symbols indicate doses of 0.5 and 1.0 mg kg⁻¹, respectively; from Hamblett et al. [7]; Copyright © 2004 American Association for Cancer Research; (d) Schematic representation of emerging ultra–high-DAR ADC platforms (APCs and ANCs).

Despite the historic developments, conventional ADCs are fundamentally constrained by drug antibody ratio (DAR) values between 2 and 8 [4], necessitating the use of highly potent payloads (IC₅₀< 1 nM; Fig. 1b) to achieve therapeutic efficacy [5]. This requirement limits payload selection, reduces dosing flexibility, and narrows the therapeutic window [6]. Efforts to increase DAR have been made in attempts to overcome these limitations. However, such approaches expose a cascade of physicochemical liabilities inherent to traditional ADC formats. In particular, hydrophobic payloads promote aggregation and rapid clearance at elevated DAR levels. As illustrated in Fig. 1c, although increasing DAR reduces IC₅₀ values in vitro, it also leads to faster in vivo clearance and diminished therapeutic performance in the authors’ reported system, as evidenced by reduced efficacy following a single 0.5 mg kg⁻¹ dose [7].

Novel ultrahigh-DAR platforms, such as antibody polymer conjugates (APCs) and antibody nanoparticle conjugates (ANCs) (Fig. 1d), have been proposed to overcome these limitations by decoupling payload loading from the antibody itself. Ultrahigh-DAR platforms are defined by their ability to carry payloads in significantly larger quantities than the 8 in ADCs. To do so, both platforms shift the drug conjugation site away from the antibody itself and onto external macromolecular structures: polymers in the case of APCs and nanoparticles in the case of ANCs. Antibodies are subsequently conjugated to the macromolecular structures to confer targeting properties [8].

APCs and ANCs are distinguished by several key features, including their size [9]. APCs typically have hydrodynamic diameters in the tens of nanometers, generally below 30 nm, [8] whereas ANCs are usually larger than 50 nm [10]. In addition, payloads in APCs are covalently conjugated to the polymer scaffold, while payloads in ANCs may be either covalently attached to or non-covalently encapsulated within the nanoparticle. From a structural perspective, APCs are molecular therapeutics that exist as individual antibody–polymer conjugates, whereas ANCs are supramolecular assemblies formed through the organization of multiple molecular components. Consequently, ANCs are best regarded as a distinct class of targeted nanomedicines rather than as simple extensions of ADCs or APCs.

Through careful polymer design, APC platforms have achieved DAR values ranging from 10 to greater than 100, significantly increasing intratumoral drug delivery without compromising targeting or pharmacokinetics [6, 10–12]. Similarly, ANCs employ nanoparticles as high-capacity payload carriers that are subsequently decorated with antibodies. These platforms offer greater flexibility in optimizing therapeutic performance [13, 14] through introducing additional tunable parameters such as particle size, composition, and surface chemistry.

In this mini review, we succinctly introduce how APCs and ANCs are designed to achieve ultrahigh-DAR values and showcase several distinct architectures. We then share our vision on the potential impact of ultrahigh-DAR therapeutic platforms and highlight potential challenges that need to be addressed in the coming years.

Antibody polymer conjugates

Design principles and synthetic strategies

Antibody–polymer conjugates (APCs) typically have payloads attached to linear hydrophilic polymers, which are then covalently attached to antibodies. The polymer functions as a reservoir for payloads while also maintaining favorable solubility and colloidal stability, permitting substantially higher loading without compromising antigen recognition or antibody pharmacology [6, 15].

Hydrophilic, biocompatible, and often non-immunogenic polymers are used in APCs. Prominent synthetic examples include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers [8, 16] and biodegradable polyacetal polymers such as Fleximer® [11]. These hydrophilic scaffolds help to mask the hydrophobic payloads and linkers, counteracting the tendency of high-DAR constructs to aggregate.

To reliably generate such copolymers with low dispersity and high chain-end fidelity, controlled polymerization methods such as reversible addition fragmentation chain-transfer polymerization are used. This low polydispersity and high chemical homogeneity are preserved when the polymers are subsequently conjugated to antibodies, which is highly desirable for quality control.

Preservation of antibody function is achieved by shifting the antibody conjugation site to defined positions away from the fragment antigen-binding (Fab) region [16]. A common strategy involves mild reduction of interchain disulfide bonds in the hinge region, followed by subsequent Michael addition of semi-telechelic polymers. This regioselective approach attaches polymer chains at defined sites, improving physicochemical properties [15, 17].

Representative high-DAR APC platforms

Several platforms illustrate how APCs can be designed with ultrahigh-DAR values, with Table 1 summarizing key parameters of the platforms highlighted in this section.

Table 1.

Summary of notable APC platforms with key parameters.

Polymer	Antibody	Payload	Payload-linker attachment	Antibody payload ratio	Ref.
HPMA	α-PD-L1	Epirubicin	Amide	40	[10]
HPMA	Daratumumab	Epirubicin	Amide	30	[8]
Dolaflexin	Trastuzumab	Auristatin F hydroxypropylamide	Amide	10–15	[11]
Dolaflexin	Rebmab200 (XMT-1535)	Auristatin F hydroxypropylamide	Amide	10–15	[18]
XTEN	αCD22	Iodo-PEG-maytansine Iodo-vc-MMAE	Carbamate	18	[20]
PLG	Anti-PD-L1	SN-38	Ester	72	[12]
Bottlebrush	Trastuzumab	SN-38	Ester	60	[6]

First, HPMA copolymer–based APCs are among the most extensively characterized due to its biocompatibility and lack of polyethylene glycol (PEG)-like immunogenicity (Fig. 2a) [16]. HPMA-based systems carrying epirubicin (EPI) that target PD-L1 have been designed to achieve DARs as high as 40 [10], while those targeting CD38 (DARA-P-EPI) were reported with DAR values of ~30 [8]. The authors showed that their constructs retained antigen binding and pharmacokinetics, with no impairment in circulation and clearance kinetics from plasma.

Figure 2.

APCs as high-DAR platforms; (a-c) representative APC designs: antibody–HPMA copolymer conjugates, adapted from Li et al. [8]; Dolaflexin platform, adapted from Yurkovetskiy et al. [11]; and XTEN-based conjugates, reproduced from Kaupbayeva et al. [21] with permission from the Royal Society of Chemistry; (d) Schematic illustration of the Myris ADC platform; reproduced from Myris Therapeutics, Inc. [23]; (e) design of ABCs, highlighting drug conjugation to the polymer side chains via click chemistry and incorporation of cleavable linkers; (f) in vivo antitumor efficacy in a low HER2 HCC70 orthotopic xenograft model, showing that SN38-HER2 ABC achieves better performance than the conventional ADC T-DXd ; adapted from Liu et al. [6]; Copyright © 2025 Springer Nature.

The Dolaflexin platform, built on a hydrophilic, fully biodegradable polyacetal carrier (PHF or Fleximer®), exemplifies another clinically advanced APC implementation (Fig. 2b). In this system, the polymer sidechain includes terminal maleimides that are used to conjugate with cysteine residues, as opposed to directly conjugating drug molecules to cysteine. Examples such as Trastuzumab–Dolaflexin and XMT-1536 typically achieved DARs values from 10 to 15 [11, 18], and the former was shown to display clearance rates similar to that of the antibody itself.

Recombinant polypeptides [19] such as XTEN extend these concepts to genetically encoded scaffolds (Fig. 2c). XTEN is an intrinsically disordered pseudo-repeating polypeptide that can be combined with cysteine-engineered THIOMAB antibodies to generate “TXC” constructs with defined DARs up to 18 [20]. As XTEN is hydrophilic and biodegradable, these APC conjugates maintain exposure profiles comparable to low DAR ADCs despite their higher payloads. Poly(L-glutamic acid) offers a further high-density platform, enabling SN38-loaded anti–PD-L1 conjugates with ultrahigh-DAR values of ≈72 without negatively affecting the Fab structure [12].

Instead of attaching the polymer to antibodies after initial synthesis (graft-to), another approach is to grow the polymer from protein surfaces (graft-from) (Fig. 2d) [21, 22]. Myris Therapeutics aims to capitalize on this latter method through protein modification via atom transfer radical polymerization initiators, which they claimed in a company announcement would allow them to build polymer bottlebrushes and achieve DAR values of 50–300 [23].

Development of ABCs

The Antibody–Bottlebrush Prodrug Conjugate (ABC) platform features an mAb covalently conjugated to the terminus of a bottlebrush prodrug (Fig. 2e). It was reported to increase DAR capacities by up to two orders of magnitude over that of traditional ADCs. The bottlebrush displays hydrophilic PEG side chains that shield the construct, while drug payloads are attached as prodrugs through cleavable linkers. Its design also tolerates dense loading compared to the aforementioned linear polymers [6].

ABCs were shown to be ~25 nm by dynamic light scattering (DLS) and cryo-electron microscopy, placing them at the intersection of polymer conjugates and nano-enabled delivery while still retaining an intact antibody for antigen recognition [6]. In the reported work, more than 10 ABCs were synthesized against targets such as human epidermal growth factor receptor 2 (HER2) or mucin 1, with payloads spanning several orders of magnitude in potency, demonstrating their flexibility as a platform.

ABCs showed strong target engagement and cellular uptake, producing tumor regression without discernible toxicities in xenograft models. Notably, ABCs carrying the clinically relevant SN-38 (DAR ≈ 60) were reported to outperform trastuzumab deruxtecan (DAR ≈ 8) in a low HER2 model at the same antibody dose (Fig. 2f). This supports the idea that ultrahigh-DAR architectures can offer a practical advantage when antigen density is limiting [6].

Across APC formats, a high DAR leads to markedly higher drug delivery into tumors compared with conventional ADCs without necessarily accelerating clearance or losing specificity [15]. Hydrophilic polymers contribute a stabilizing, “stealth-like” effect that reduces premature systemic elimination [6]. As payload capacity is no longer the primary constraint, APCs can accommodate small molecule drugs with moderate cytotoxicity and improved safety profiles, or even other drug formats such as siRNA, protein degraders, or peptides [2, 6, 10]. However, these larger scaffolds may have bulky polymer domains that introduce steric hindrance and reduce binding, especially at very high DARs or under conditions where binding avidity is reduced [16].

Antibody nanoparticle conjugates

Small molecule payloads

Unlike conventional ADCs that rely on small molecular constructs to carry cytotoxic payloads, antibody–nanoparticle conjugates (ANCs) use much larger nanoparticles (NPs) as delivery vehicles, typically ranging from 10 to >100 nm in diameter [24]. Their substantially larger internal volume allows them to encapsulate or carry far higher numbers of payload molecules than traditional ADCs [25].

Although each nanoparticle carries a large number of payload molecules, its surface can also be functionalized with many antibodies. In this case, calculation of a DAR value requires estimating both (1) the number of molecules encapsulated within each nanoparticle, as well as (2) the number of antibodies on the nanoparticle surface. Due to the supramolecular nature of ANCs, estimating both values is non-trivial. Hence, additional quantification metrics, such as drug loading by weight percentage (wt%), are often used instead [26], where values ≥10 wt% are considered high.

Nonetheless, the overall DAR typically exceeds that of conventional ADCs (≥8) when calculated, enabling very high payload densities and can theoretically exceed 1000 in some cases [25, 27]. The NP component can be architecturally diverse, ranging from purely organic materials (Fig. 3a), such as polymeric nanoparticles and liposomes, to hybrid constructs incorporating inorganic cores, such as silica or metal NPs [14].

Figure 3.

ANCs as high-DAR platforms; (a) representative ANCs based on organic nanocarriers for the delivery of small-molecule payloads; (b) schematic of in vivo CAR-T therapy, enabled by targeted lipid nanoparticles carrying mRNA payloads; reproduced from Rurik et al. [28]; Copyright © 2022 The American Association for the Advancement of Science; (c) representation of Protein-Antibody Conjugates (PACs) together with their chemical design; adapted from Liu et al. [27]; Copyright © 2021 Wiley-VCH GmbH; (d) representation of Antibody-Directing AntibodyConjugates (ADACs) together with their chemical design; adapted from Gong et al. [29]; Copyright © 2024 Wiley-VCH GmbH.

Payloads are loaded through non-covalent interactions in most cases, although covalent attachment strategies are also employed depending on the chemistry and desired release profile [28]. A summary of notable ANC designs covered in this section may be found in Table 2.

Table 2.

Summary of notable ANC platforms with key parameters.

Antibody nanoparticle conjugates	Antibody	Payload	Payload loading method	Loading	Ref.
Liposomes	Fab′ of cetuximab	Pegylated liposomal doxorubicin (Doxil)	Noncovalent encapsulation	30 μg Fab′ μmol−1 (phospholipid)	[29]
Polylactic acid nanoparticle	Trastuzumab (Herceptin)	Paclitaxel	Noncovalent encapsulation	248 Ab NP−1	[30]
Polylactic acid nanoparticle	Trastuzumab (Herceptin)	Docetaxel (DTX)	Noncovalent encapsulation	94.0% Ab binding efficiency	[31]
DAN-222	Unreported	Camptothecin	Unreported	Unreported	[32]
DAN-311	Trastuzumab	Camptothecin	Covalent	60	[33]
K-679	Cetuximab	DM1	Covalent	40	[34]
PEG-P(TMC-DTC) nanoparticle	Daratumumab	Vincristine sulfate	Electrostatic encapsulation	Up to 8.7 Ab NP−1	[35]
Block ionomer complex	mAbCx43	Cis-platin	Metal coordination	100 μg Ab mg−1 nanogel	[36]
PEG-P (TMC-DTC	Anti-CD44	DM1	Disulfide	Up to 9.8 Ab NP−1	[37]
Albumin carrier	Bevacizumab	Nab-paclitaxel (Abraxane)	Noncovalent coating	Unreported	[38]
PEG-based nanoparticle	Trastuzumab	RNaseA	Boronic ester	60	[44]
PEG-coated silica nanoparticles	Anti-CD4	RNaseA	Boronic ester	41	[27]

Early ANC examples include liposomes for small-molecule drug delivery [29], which have largely been supplanted by lipid nanoparticles (LNPs) in nucleic acid therapies [14]. Biodegradable polymer-based NPs have also been widely used. For instance, paclitaxel palmitate was non-covalently encapsulated in poly(D,L-lactic acid) NPs at a loading of 7.8 wt% [30], followed by non-covalent attachment of anti-HER2 antibodies at 248 Ab NP⁻¹. Similarly, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) NPs functionalized with trastuzumab (Herceptin, HCT) achieved ~5.2 wt% loading [31], with three functionalization strategies tested: passive adsorption, charged adsorption, and covalent bioconjugation. The latter two methods showed better HCT stability on particle surfaces when stored at 4°C. These examples highlight the versatility of ANCs in combining payload encapsulation with antibody-mediated targeting.

Several clinically relevant polymer-based ANC platforms have been reported. The startup Dantari developed DAN-222 and DAN-311 to deliver camptothecin. DAN-222 completed a dose-escalation Phase 1 trial (NCT05261269) with encouraging results reported in a poster abstract [32], while DAN-311 was reported in a conference abstract to achieve a DAR of 60 using trastuzumab for targeting [33], demonstrating the potential for ultrahigh-DAR therapeutics in clinical translation.

Another design reported in a 2025 abstract is the antibody drug–loaded unimicelle (unimer–micelle) conjugate (ADUC), K-679 [34]. In this system, single-chain polymers are conjugated to antibodies and subsequently assembled into nanoparticle structures capable of carrying therapeutic payloads. Notably, this platform achieves a DAR of ~40, highlighting its potential as a high-loading delivery strategy.

Other nanoparticle platforms include immunopolymersomes (IPs), which have been used to deliver vincristine sulfate via electrostatic interactions [35]. Reported DAR values ranged from 2.2 to 8.7 per IP, with a DAR of 4.4 yielding the highest cellular uptake, 6.4-fold greater than unconjugated controls. Cisplatin-loaded nanogels have achieved 30%–35% drug loading for targeting high-grade gliomas, with 100 μg of antibody per mg of nanogel [36]. Covalent strategies have also been demonstrated; e.g. mertansine (DM1) was coupled via disulfide bonds to vesicle membranes, followed by anti-CD44 antibody functionalization, achieving a DAR of 275 with an optimized antibody density of 5.0. The resulting particles were shown to selectively release DM1 upon GSH exposure and not under physiological conditions [37]. Protein-based nanoparticles are another emerging approach, exemplified by albumin nanoparticles delivering paclitaxel (AB160) with non-covalent bevacizumab coating to target vascular endothelial growth factor-expressing cells, with a tumor response rate of 36.8% among 19 patients with measurable disease [38].

Macromolecular payloads

Using ANCs, cargo delivery is not limited to small-molecule drugs but can also include nucleic acids and proteins (Fig. 3b). This provides a distinct advantage, as direct conjugation of nucleic acids or proteins to antibodies is typically limited to a 1:1 or 1:2 antibody–payload ratio. Using antibody-targeted LNPs for industrial applications has been reviewed in 2024, along with CMC considerations [39].

Multiple studies have reported on conjugating antibodies to mRNA-loaded LNPs to achieve specific in vivo delivery [40, 41]. By targeting T cells, it is also possible to produce CAR-T cells in vivo, potentially offering a more scalable and affordable treatment for cancer, autoimmune diseases, and cardiac injuries [42, 43].

For alternative payloads such as proteins (Fig. 3c, d), a protein-to-antibody ratio (PAR) was used as a quantification metric [27, 44]. For example, a subclass of antibody-directing antibody conjugate nanogels (Fig. 3d) has been reported to efficiently deliver intrabodies into the cytosol [44]. Control studies showed negligible passive uptake, attributed to the high density of PEG moieties in the nanogel. The PAR was ~60 for the HER2-RNaseA nanogel at 20% trastuzumab decoration.

A related strategy, protein–antibody conjugates (PACs) [27], employs silica nanoparticles decorated with functional polymers. Using two orthogonal click chemistries, these polymers can be conjugated with both antibodies and payloads. The PAR was estimated to be 15 and 41 for PACs loaded with GFP and RNaseA, respectively, corresponding to 7% and 10% loading capacities.

In both studies, control experiments indicated that passive uptake was minimal compared to antibody-functionalized nanoparticles, due to the antifouling properties of PEG in the polymer-based nanostructures [45]. This approach enables receptor-specific cellular uptake while minimizing off-target toxicity and macrophage-mediated clearance.

Translational challenges of APCs and ANCs

Although much progress has been made for both ultrahigh-DAR platforms, there remain challenges that hinder translation. Due to the narrower focus of this mini review, readers are referred to full-length reviews for coverage on APCs [46] and ANCs [47], as well as how they compare with ADCs [46, 48].

On the manufacturing side, ligand attachment may be limited by lower conjugation efficiency compared with conventional ADCs [49]. This may be attributed to the larger steric hindrance between the antibody and the large polymer or nanoparticle scaffolds compared to a small-molecule drug. In addition, the multi-step syntheses involved in preparing the payload for optimal polymer conjugation (in both APCs and ANCs) and subsequent encapsulation (in ANCs) may introduce manufacturing complexities that require additional validation.

Next, both the ligand density as well as the type of ligand on ANCs have a critical impact on their therapeutic efficacy by influencing their diffusional properties in tumor tissue and reticuloendothelial system clearance behavior [50].

The supramolecular assembly process in ANCs necessarily means that batch-to-batch reproducibility is reduced [14] compared to molecularly well-defined species, as contemporary characterization techniques capture ensemble rather than individual properties. This lack of simple and reliable analytical tools to quantify the number of ligands per nanoparticle for organic assemblies as opposed to inorganic ones further complicates matters [50].

Beyond synthetic challenges, there are also gaps between preclinical studies and clinical evaluation. For instance, protein coronas may form on both APCs [51] and ANCs after administration [52, 53], which can negatively influence nanoparticle stability, pharmacokinetics, and receptor-specific uptake. Moreover, this corona can mask the nanomedicines’ surface, reducing their targeting ability by hindering interactions between their ligands and receptors. The corona’s heterogeneity also makes it difficult to predict exact in vivo behaviors of the administered nanomedicine.

As constructs get larger in size, their tumor-penetrating ability typically gets weaker, with optimal sizes suggested as ranging between 5 and 35 nm. Thus, ANCs are likely to be more impacted than APCs in this aspect. Their biodistribution (right tissue, right target) upon administration is also a key determinant of clinical translation and requires close examination in pre-clinical settings [54].

The orientation of the antibody on the surface is critical for maintaining targeting efficiency. Site-specific conjugation strategies are therefore needed to improve product homogeneity and therapeutic efficacy, moving beyond stochastic lysine- or thiol-based approaches [55]. One such strategy uses a covalent inhibitor of CD38 (part of the ADP-ribosyl cyclase family) to attach a wide variety of payloads modified with the inhibitor 2′-Cl-araNAD⁺ directly onto both antibodies [56] and the exterior of exosomes [57]. In the former case, the CD38 modifications were performed directly on antibodies, and the authors reported a maximum DAR of 8. In the latter, they acknowledged the heterogeneous composition of derived exosomes and did not quantify the number of CD38 per exosome.

Additionally, for ANC platforms, overall pharmacokinetics may largely be dominated by the nanoparticle carrier rather than the antibody [10], which can diminish the beneficial circulation properties typically conferred by the antibody.

The immunogenic potential of APCs and ANCs also requires rigorous assessment to improve clinical translation success. The immunogenicity of PEG is likely the most well-documented, but antibodies can also be generated against other components such as nanoparticle core, terminal groups, and surface coatings [58].

Finally, these high-DAR systems may also interact with other cellular processes in unforeseen manners. For instance, the mTOR signaling pathway has been reported to be heavily involved in regulating metabolic pathways [59]. Internalization of APCs and ANCs could substantially impact these processes, including lysosomal biogenesis, degradation, and autophagy, which could influence payload processing and therapeutic efficacy. As of 2025, there are several ANCs in clinical trials [60], but no APCs or ANCs have reached the commercial market, highlighting the need for further clinical validations on these high-DAR platforms.

Conclusion and future outlook

Therapeutic platforms with ultrahigh DAR offer substantial advantages by enabling greater payload delivery while preserving antigen targeting and pharmacokinetics. In this mini-review, we discussed APCs and ANCs as two major architectures capable of achieving ultrahigh DAR. Both approaches share a central design principle: maintaining overall hydrophilicity to minimize aggregation driven by hydrophobic payloads, which is a key limitation in traditional high-DAR ADCs.

In APCs, polymers act as versatile payload carriers and can be engineered to mask hydrophobic drugs while maintaining solubility and targeting. Examples include HPMA-based polymers [16], Dolaflexin systems [11], recombinant polypeptides [20], and bottlebrush prodrug conjugates [6]. Beyond these synthetic polymers, biologically derived polymers such as poly-ADP-ribose (PAR) may also be used in future therapeutics. It has been reported to be a versatile platform in diversifying payloads beyond traditional chemotherapy molecules, such as proteins [61] and antibodies [62].

In contrast, ANCs leverage larger, amphiphilic nanostructures to carry diverse cargos. They allow tuning of many parameters including size, composition, surface chemistry, and targeting ligands, broadening the scope of potential therapeutic payloads.

Beyond carrying small chemotherapy molecules, larger payloads may also be viable for APCs and ANCs, including proteins [51], nucleic acids [63], and protein degraders [64]. The modularity enabled by the polymer in APCs allows for easy access to combination payload strategies, while the larger volume of nanoparticles permits encapsulation of these larger payloads. The antibody can also be chosen to have immunomodulation properties such as immune checkpoint inhibitors (anti-PD-1/PD-L1 and anti-CTLA-4) [65].

Overall, high-DAR and PAR platforms offer remarkable modularity, payload versatility, and tunable pharmacokinetics, making them a promising foundation for next-generation antibody therapeutics. Continued advances in polymer chemistry, nanomaterial design, and site-specific conjugation strategies are expected to expand their clinical potential, enabling safer and more effective therapies across oncology and beyond.

Author contributions

Haosheng Feng (Writing—original draft [equal], Writing—review & editing [equal]) and Bin Liu (Conceptualization [equal], Funding acquisition [equal], Supervision [equal], Writing—original draft [equal], Writing—review & editing [equal])

Conflicts of interest

The authors declare no conflict of interest.

Funding

The presented work was kindly supported by the Cancer Prevention & Research Institute of Texas (CPRIT) Multi-Investigator Research Award (MIRA) PILOT PROJECTS (RP240439) and the University of Houston’s new faculty startup funds and DDI seed grant.

Data availability

No new data were generated or analyzed in support of this research.

Ethics and consent statement

No consent was required.

Animal research statement

Not applicable.