Table 1.
Avidity-based therapeutic antibody concepts in the clinic and engineering platforms
| Agent (company) | Target | Format | Indication (selected) | Development status (selected trials) |
|---|---|---|---|---|
| Targeting multiple epitopes | ||||
| Sym015 (Symphogen) | MET | Mixture of two IgG1 antibodies binding non-overlapping epitopes on the Semaphorin domain of MET | Solid tumours (NSCLC) | Phase IIa completed (NCT02648724) |
| REGN5093 (Regeneron) | MET | Biparatopic, bispecific IgG4 antibody targeting two non-overlapping epitopes on MET (Veloci-Bi bispecific technology) | Solid tumours (NSCLC) | Phase I/II (NCT04077099) |
| REGN5093-M114 (Regeneron) | MET | Biparatopic, bispecific IgG4 antibody targeting two non-overlapping epitopes on MET (Veloci-Bi bispecific technology) conjugated to a maytansinoid | Solid tumours (NSCLC) | Phase I/II (NCT04077099) |
| Sym004 (Symphogen) | EGFR | Mixture of two IgG1 antibodies (futuximab, modotuximab) binding non-overlapping epitopes on EGFR | Solid tumours (mCRC) | Phase III completed (NCT02083653) |
| KN026 (Alphamab) | HER2 | Biparatopic, bispecific IgG1 antibody targeting two non-overlapping epitopes on HER2 (CRIB technology) | Solid tumours (breast and gastric cancer) | Phase I (NCT03619681, NCT03847168) |
| MBS301 (Beijing Mabworks Biotech) | HER2 | Afucosylated, biparatopic, bispecific IgG1 antibody targeting two non-overlapping epitopes on HER2 (knobs-into-holes bispecific technology) | Solid tumours (HER2+) | Phase I (NCT03842085) |
| Zanidatamab, ZW25 (Zymeworks) | HER2 | Biparatopic, bispecific IgG1 antibody targeting two non-overlapping epitopes on HER2 (Azymetric bispecific technology) | Solid tumours (HER2+) | Phase II (NCT04466891, NCT03929666, NCT04224272) |
| ZW49 (Zymeworks) | HER2 | Biparatopic, bispecific IgG1 antibody targeting two non-overlapping epitopes on HER2 (Azymetric bispecific technology) conjugated to a maytansinoid (Zymelink antibody-drug condensate technology) | Solid tumours (HER2+) | Phase I (NCT03821233) |
| REGN-COV, casirivimab/imdevimab (Regeneron) | SARS-CoV-2 spike | Mixture of two human IgG1 antibodies, binding non-overlapping epitopes on the SARS-CoV-2 viral spike | COVID-19 | EUA, Phase III completed (NCT04381936) |
| Evusheld, tixagevimab/cilgavimab, (AstraZeneca, VanderBilt) | SARS-CoV-2 spike | Mixture of two human IgG1 antibodies with mutations that extend half-life (M252Y,S254T,T256E) and reduce Fc receptor and C1q interactions (L234F, L235E, P331S), binding non-overlapping epitopes on the SARS-CoV-2 viral spike | COVID-19 | EUA, Phase III (NCT04625725) |
| BMS-986414/BMS-986413 (Bristol Myers Squibb/Rockefeller University) | SARS-CoV-2 spike | Mixture of two human IgG1 antibodies with mutations that extend half-life (M428L/N434S), binding non-overlapping epitopes on the SARS-CoV-2 viral spike | COVID-19 | Phase II/III (NCT04518410) |
| ADM03820 (Ology Bioservices) | SARS-CoV-2 spike | Mixture of two human IgG1 antibodies binding non-overlapping epitopes on the SARS-CoV-2 viral spike | COVID-19 | Phase I (NCT04592549) |
| SAR441236 (Sanofi) | HIV-1 envelope | Triparatopic IgG1 bNAb from the VRC01-LS, PGDM1400 and 10E8v4 therapeutic antibodies, targeting the CD4bs, gp41 MPER and V1/V2 glycan-directed binding sites on HIV-1 (CODV-Ig technology) | HIV-1 | Phase I (NCT03705169) |
| Inmazeb, atoltivimab/maftivimab/odesivimab (Regeneron) | Zaire ebolavirus (ZEBOV) glycoprotein | A mixture of three afucosylated IgG1 antibodies that each bind to different, non-overlapping epitopes on the ZEBOV glycoprotein | ZEBOV | Approved (NCT03576690) |
| Targeting multiple cell surface receptors | ||||
| LAVA-051 (Lava Therapeutics) | CD1d, Vδ2 TCR | A trispecific γδ T cell engager comprised of a single-domain antibody (VHH) that binds both CD1d and the iNKT TCR, and a VHH targeting the Vγ9Vδ2 TCR, which triggers iNKT and Vγ9Vδ2 T cell activation | Haematologic malignancies (CLL, MM, AML) | Phase I /II (NCT04887259) |
| Sym013 (Symphogen) | EGFR, HER2, HER3 | A mixture of six humanized monoclonal IgG1 antibodies (three pairs) that bind to non-overlapping epitopes on EGFR, HER2 and HER3 | Advanced epithelial malignancies | Phase I/II terminated (NCT02906670) |
| Tuning antibody valency | ||||
| IGM-8444 (IgM Biosciences) | DR5 | Pentameric IgM antibody with ten binding sites specific for DR5 | Solid tumours | Phase I (NCT04553692) |
| INBRX-109 (Inhibrx) | DR5 | Four single-domain antibodies (tetravalent) fused to an Fc domain (sdAb technology; binding units derived from heavy-chain-only antibodies) | Solid tumours | Phase I (NCT03715933, NCT04950075) |
| INBRX-106 (Inhibrx) | OX40 | Six single-domain antibodies (hexavalent) fused to an Fc domain (sdAb technology; binding units derived from heavy-chain-only antibodies) | Solid tumours | Phase I (NCT04198766) |
| ABBV-621, APG350, Eftozanermin alpha (Abbvie/Apogenix) | TRAIL | Hexavalent TNFRSF agonist comprising a fusion protein composed of three receptor binding domains in a single chain arrangement, linked to a silenced human IgG1 Fc-domain (HERA-ligand technology) | Multiple myeloma | Phase Ib (NCT04570631) |
| PF-06755347, GL-2045 (Pfizer/Gliknik) | C1q | Recombinant human IgG1-based Fc multimer; fusion of the complete IgG1 hinge-CH2-CH3 coding region to the IgG2 hinge region (Stradomer technology) | Autoimmune diseases | Phase I (NCT03275740) |
| Tuning antibody oligomerization | ||||
| GEN3014, HexaBody-CD38 (Genmab) | CD38 | IgG1 antibody containing an E430G hexamerization-enhancing Fc mutation (HexaBody technology) | Haematologic malignancies (MM) | Phase I/II (NCT04824794) |
| Targeting multiple epitopes and tuning antibody oligomerization | ||||
| GEN3009, DuoHexaBody-CD37 (Genmab/AbbVie) | CD37 | Biparatopic, bispecific IgG1 antibody targeting two non-overlapping epitopes on CD37 containing an E430G hexamerization-enhancing Fc mutation (DuoHexaBody technology) | Haematologic malignancies (B cell NHL, CLL) | Phase I /II (NCT04358458) |
| GEN1029, HexaBody DR5/DR5 (Genmab) | DR5 | Mixture of two IgG1 antibodies targeting non-overlapping epitopes on DR5, both containing an E430G hexamerization-enhancing Fc mutation (HexaBody technology) | Solid tumours | Phase I (terminated) (NCT03576131) |
| Tuning binding to Fc effector receptors | ||||
| GS-1811, JXT-1811 (Gilead Sciences/Jounce Therapeutics) | CCR8 | IgG1 antibody afucosylated for enhanced ADCC | Solid tumours | Phase I (NCT05007782) |
| BMS-986340 (Bristol Myers Squibb) | CCR8 | IgG1 antibody afucosylated for enhanced ADCC | Solid tumours | Phase I (NCT04895709) |
| SEA-CD70 (Seattle Genetics) | CD70 | IgG1 containing afucosylated for enhanced ADCC (SEA technology) | Myeloid malignancies (MDS, AML) | Phase I (NCT04227847) |
| Elipovimab, GS-9722 (Gilead Sciences) | HIV-1 envelope | IgG1 bNAb (derived from PGT121) containing S239D/I332E and M428L/N434S Fc mutations for improved PK, enhanced ADCC and ADCP (high cytotoxicity XmAb and Xtend Fc domain technology) | HIV-1 | Phase Ib (GS-US-420-3902a) |
| Monjuvi, tafasitamab (MorphoSys/Incyte) | CD19 | IgG1 antibody containing S239D/I332E Fc mutations for enhanced ADCC and ADCP (high-cytotoxicity XmAb Fc domain technology) | Haematologic malignancies (DLBCL) | Approved |
| Margenza, margetuximab (Macrogenics) | HER2 | IgG1 antibody containing L235V/F243L/R292P/Y300L/P396L Fc mutations for enhanced ADCC | Solid tumours (HER2+ breast cancer) | Approved |
| Poteligeo, mogamulizumab (Kyowa Hakko Kirin) | CCR4 | IgG1 antibody afucosylated for enhanced ADCC (Potelligent Technology) | Adult T cell leukaemia or lymphoma | Approved |
| Gazyva, obinutuzumab (Roche) | CD20 | IgG1 antibody afucosylated for enhanced ADCC (GlycoMab Technology) | Haematologic malignancies (CLL, FL) | Approved |
| Fasenra, benralizumab (Astra Zeneca/Kyoa Hakko Kirin) | IL-5Rα | IgG1 antibody afucosylated for enhanced ADCC (Potelligent Technology) | Asthma | Approved |
| Targeting multiple cell surface receptors and tuning binding to Fc effector receptors | ||||
| Rybrevant, amivantamab (Janssen/JNJ) | EGFR, MET | IgG1 bispecific antibody afucosylated for enhanced ADCC (DuoBody technology) | Solid tumours (metastatic NSCLC with EGFR exon 20 insertion mutations) | Approved |
| MCLA-129 (Merus/Betta pharmaceuticals) | EGFR, MET | IgG1 bispecific antibody afucosylated for enhanced ADCC (Biclonics and GlymaxX technology) | Solid tumours (NSCLC) | Phase I/II (NCT04868877) |
Data available as of 1 May 2022. Engineering data were obtained from public documents (scientific literature, abstracts, posters and patent publications). This overview table excludes clinical programmes investigating bispecific antibodies, for which we refer to Labrijn et al.20. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; AML, acute myeloid leukaemia; bNAb, broadly neutralizing antibody; CCR, CC-chemokine receptor; CLL, chronic lymphocytic leukaemia; CODV-Ig, crossover dual variable Ig-like protein; COVID-19, coronavirus disease 2019; CRIB, charge repulsion-induced bispecificity; DLBCL, diffuse large B cell lymphoma; DR5, death receptor 5; EGFR, epidermal growth factor receptor; EUA, emergency use authorization; Fc, crystallizable fragment; FL, follicular lymphoma; HER2, human epidermal growth factor receptor 2; iNKT cell, type I natural killer T cell; mCRC, metastatic colorectal cancer; MDS, myelodysplastic syndrome; MET, tyrosine-protein kinase MET; MM, multiple myeloma; MPER, membrane-proximal external region; NHL, non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sdAb, single-domain antibody; TCR, T cell receptor; TNFRSF, tumour necrosis factor receptor superfamily; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; VHH, variable domain of a heavy chain-only antibody. aAdinsight entry, trial not listed in ClinicalTrials.gov.