Table 2.
Anti-ICPML compounds with enhanced target cell-depleting potential reported in the literature and/or in clinical development.
| Compound | Type of Construct | Preclinical or Clinical (ClinicalTrials.gov Identifier, Phase, Comments) Development | References |
|---|---|---|---|
| Antibodies with enhanced constitutive effector functions | |||
| Anti-B7-H3 (eroblituzumab/MGA271) | mAb with mutated Fc domain | Clinical: NCT01391143, phase I; NCT02381314, phase I, plus ipilimumab; NCT02982941, phase I in children; NCT02475213, phase I, plus pembrolizumab; NCT02923180, phase II, neoadjuvant in prostate cancer; NCT04129320, NCT04634825, phase II/III, plus anti-PD-1 mAb or bispecific anti-PD-1xLAG-3 mAb. | [130] |
| Anti-CD70 (cusatuzumab/ARGX-110) | Afucosylated mAb | Clinical: NCT03030612, NCT04264806, NCT04241549, NCT04150887, NCT04023526, phase I/II, plus AZA or venetoclax in MDS, AML, CML; NCT02759250, phase I in NPC; NCT01813539, phase I/II neoplasms. | [135,144] |
| ADCs | |||
| Anti-CD70 (SGN-75) | Humanized anti-CD70 mAb linked to tubulin inhibitor auristatin | Clinical: NCT01015911, phase I in NHL, RCC, modest single-agent activity; NCT01677390, phase Ib, plus everolimus in RCC. | [145,146] |
| Anti-CD70 (SGN-CD70A) | Anti-CD70 mAb linked to PBD dimer | Clinical: NCT02216890, phase I in NHL, RCC, showed modest single-agent activity and high frequency/severity of thrombocytopenia. | [147,148] |
| Anti-CD70 (BMS-936561/ MDX-1203) | Human anti-CD70 mAb linked to duocarmycin derivative | Clinical: NCT00944905, phase I in NHL, RCC. | [149,150] |
| Anti-B7-H3 (MGC018) | Humanized anti-B7-H3 mAb linked to duocarmycin | Clinical: NCT03729596, phase I/II, plus anti-PD-1 in several solid tumors. | [151] |
| Anti-B7-H3 (m276) | Human anti-B7-H3 mAb linked to PBD dimer | Preclinical: It depleted both B7-H3+ tumor cells as well as B7-H3+ tumor endothelial cells leading to the eradication of established tumors. Moderate expression of B7-H3 was detected also on normal tissues. | [131] |
| Anti-B7-H3 | Anti-B7-H3 mAb linked to chlorin e6 for photodynamic therapy | Preclinical | [152] |
| Anti-B7-H4 (h1D11 TDC) | PBD linked to engineered cysteines of an anti-B7-H4 mAb via a protease-labile linker. | Preclinical: This ADC induced durable regression in different mouse models of TNBC. | [153] |
| anti-TIM-1 (CDX-014) | Human anti-TIM-1 linked to MMAE | Clinical: NCT02837991, phase I in RCC, development now discontinued. | [139] |
| Anti-PD-L1 (STM-108) | Mab anti-glycosylated PD-L1 linked to MMAE | Preclinical: Induced bystander killing on PD-L1- tumor cells. | [154] |
| Anti-PD-L1 | scFv-PD-L1 linked to the maytansinoid DM1 | Preclinical: Specific binding to PD-L1+ tumor cells and antiproliferative activity in vitro. | [155] |
| Anti-PD-L1 (atezolizumab) | Atezolizumab linked to doxorubicin | Preclinical: Induced cell killing, disruption of tumor spheroids and induced apoptosis in a breast cancer cell line. | [156] |
| Bispecific Antibodies | |||
| Anti-B7-H3xanti-CD3 | Preclinical: MEK inhibitor trametinib augmented expression of B7-H3. Combined therapy (trametinib + bispecific mAb) increased T cell infiltration and significantly suppressed tumor growth. | [30] | |
| Anti-B7-H3xanti-CD3 | Preclinical: On hematological tumor cells, redirected T cells exhibited significant cytotoxicity, secreted more cytokines and granzyme B and expressed higher levels of activating marker CD69 compared to non-redirected T cells. | [157] | |
| Anti-B7-H3xanti-CD3 | Preclinical: On cells of ENKTCL redirected T cells killed tumor cells in vitro and suppressed the growth of NKTCL tumors in mouse models. | [158] | |
| Anti-B7-H4xanti-CD3 (mAb clone #25xOKT3) | Two constructs: one Fab (anti-B7-H4) xscFv (anti-CD3),one scFvxscRv | Preclinical: In a humanized mouse model of breast cancer the bispecific Ab had strong antitumor activity and promoted the infiltration of CD8+ CTLs into the tumor without any adverse effects over the long term. | [159] |
| Anti-CD155xanti-CD3 | Preclinical | [160,161] | |
| CAR T or NK Cells | |||
| Anti-PD-L1 CAR T cells | T cells expressing theextracellular domain of human PD-1 or the scFv of an anti-PD-L1 | Preclinical: Induced regression of established PDAC cancer by >80% in both xenograft and orthotopic models. | [162] |
| Anti-B7-H3 CAR T cells (376.96 mAb) | Preclinical: Control of the growth of PDAC, ovarian cancer and neuroblastoma in xenograft mouse models and in a syngeneic tumor model without toxicity. | [132] | |
| Anti-B7-H3 CAR T cells | scFv from an anti-B7-H3 mAb + PD-1 decoy receptor. | Preclinical: Potent antitumor activity in B7-H3+/B7-H1+ tumors in vivo. | [163] |
| Anti-B7-H3 CAR T cells | scFv derived from the anti-B7-H3 mAb enoblituzumab | Preclinical: Regression of established solid tumors in xenograft models. Efficacy dependent upon high surface antigen density on tumor tissues. | [164] |
| Anti-B7-H3 CAR NK cells (CAR-NK-92MI) | Preclinical: Inhibition of tumor growth in mouse xenografts of NSCLC and prolonged survival of mice. | [165] | |
| Anti-B7-H4 CAR T cells | Preclinical: Inhibition of growth of B7-H4+ human ovarian tumor xenografts, but lethal toxicity was observed 6-8 weeks after therapy due to expression of B7-H4 in ductal and mucosal epithelial cells in normal tissues. | [166] | |
| Anti-CD47 CAR NK cells | scFv from an anti-CD47 mAb | Preclinical: Inhibition of pancreatic xenograft tumor growth after intratumoral injection in mice. | [167] |
| Anti-CD70 CAR T cells | Anti-human and -mouse CD70 CAR T cells | Preclinical: Both human and mouse anti-CAR T cells induced regression of established GBM in xenograft and syngeneic models. | [168] |
| Anti-CD70 CAR T cells | Truncated CD27, the CD70 receptor, is the CD70 binder | Preclinical: Elimination of CD70-positive HNSCC cells. | [169] |
| Anti-CD70 CAR T cells | Truncated CD27, the CD70 receptor, was used as CD70 binder | Preclinical: Adoptively transferred anti-CD70 CAR T cells induced regression of established murine xenografts. | [170] |
| Anti-CD70 CAR T cells | Clinical: NCT04662294, phase I in AML, MM, NHL | N.A. | |
| Anti-CD70 CAR T cells | Clinical: NCT03125577, NCT04429438, phase I/II in hematological B-cell malignancies. | N.A. | |
| Anti-CD70 CAR T cells (CTX130) | Anti-CD70 allogeneic T cells. | Clinical: NCT04502446, phase I in relapsed or refractory T or B cell malignancies. | N.A. |
| Antibodies Inducing Cell Death Independently of Effector Functions | |||
| Anti-CD40 mAb (dacetuzumab) | Preclinical: Dacetuzumab + anti-CD20 mAb rituximab gave synergistic apoptotic effects on NHL cells through distinct, but complementary apoptotic signal transduction pathways. | [142] | |
| Anti-CD47 (mAb AO-176) | Clinical: NCT03834948, phase I/II, alone or with paclitaxel in solid tumors; NCT04445701, phase I/II alone or with bortezomib in MM.Preclinical: Induced tumor cell phagocytosis and cytotoxicity on human tumor cells but not normal cells. | [171] | |
| Anti-CD47 mAb Ad22 | Preclinical: Ad22 induced apoptosis of Jurkat cells and preactivated PBMC | [172] | |
| Anti-CD47 (mAb CC2C6) | Preclinical: Soluble CC2C6 induced apoptosis of T-ALL cells, restored phagocytosis, and synergized with low-dose chemotherapeutics to induce apoptosis. | [173] | |
| Anti-CD47 (mAb B6H12.2) | Preclinical: Enhanced phagocytosis of a set of human pancreatic CSCs and directly induced apoptosis in the absence of macrophages. | [174] | |
| Anti-galectin 9 (mAb P4D2) | Preclinical: Induced MM cell apoptosis, inhibited tumor growth and reduced tumor infiltration of M2 macrophages. | [64] | |
| Aptamers | |||
| Anti-PD-L1 aptamer-drug conjugate | Aptamer-paclitaxel conjugate | Preclinical: The anti-PD-L1 aptamer inhibited PD-1/PD-L1 interaction and restored T-cell function. The conjugate inhibited proliferation of PD-L1-overexpressing TNBC cells. | [175] |
| Oncolytic Virus | |||
| Oncolytic virus binding to CD155 | Neuroattenuated poliovirus strain PVSRIPO that replicates in and kills only tumor cells | Clinical: NCT03564782, NCT03712358, NCT02986178, NCT03043391, NCT01491893, phase I/II in invasive breast cancer, melanoma, GBM; NCT04479241, NCT04577807, NCT04690699, phase II plus anti-PD-1or -PD-L1 in GBM, melanoma or other solid tumors. | [176,177,178] |
Abbreviations: Ab, antibody; AML, acute myeloid leukemia; AZA, azacytidine; CAR, chimeric antigen receptor; CML, chronic myeloid leukemia; CSC, cancer stem-like cell; CTL, cytotoxic T-lymphocyte; ENKTCL, Extranodal nasal natural killer (NK)/T cell lymphoma; Fc, fraction crystallizable, GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; LAG-3, lymphocyte-activation gene 3; mAb, monoclonal antibody; MDS, myelodysplastic syndrome; MM, multiple myeloma; MMAE, monomethyl auristatin E; NHL, non-Hodgkin lymphoma; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; PBD, pyrrolobenzodiazepine; PBMC, peripheral blood mononuclear cells; PD-1, programmed cell death protein 1; PD-L1, PD ligand 1; RCC, renal cell carcinoma; scFv, single-chain fragment variable; T-ALL, T-cell acute lymphoblastic leukemia; TIM-1, TIM-1, T-cell immunoglobulin and mucin domain 1; TNBC, triple-negative breast cancer.