Table 1.
Bispecific antibodies.
| Therapeutic agents | Molecular/Immune cell targets | Immune response | Notes | Ref. |
|---|---|---|---|---|
| MCLA-128 | NK cells, monocytes, macrophages, DCs HER2, HER3 FcγR |
TCMC, ADCC, enhanced HER2 uptake by DCs | IgG-like BsAb. Phase I/II study CBR 70%, good safety profile. Ongoing phase II trial: cohort 1 MCL-128 + trastuzumab/CT in HER2+; cohort 2 MCL-128 + ET in ER+/low HER2 BC [NCT03321981] | [[89], [90], [91], [92]] |
| ZW25 | NK cells, monocytes, macrophages, DCs HER2-ECD4, HER2-ECD2 FcγRs, |
TCMC, ADCC, enhanced HER2 uptake by DCs, | IgG-like BsAb. Phase I trial in pretreated HER2+ tumors. CBR: 50% | [93,111] |
| GBR1302 | HER2, CD3/T cells | TCMC | HER2 x CD3 BITE. Ongoing phase I trial in pretreated HER2+ tumors. Most common AEs: IRR/CRS | [95] |
| p95HER2xCD3 BsAb T cell | p95HER2 CD3 T cells |
TCMC | In vitro evidence. No toxicity on normal cells |
[96] |
| Tribody [(HER2)2xCD16] | HER2, FcγRIIIa NK cells, γδ T cells, monocytes, macrophages, DCs |
ADCC enhanced HER2 uptake by DCs, TCMC | Tribody mAb modification of the HER2 single-chain variable fragment domain producing an antiHER2 scFv and IFNγ fusion protein. In vitro evidence. | [[97], [98], [99], [100]] |
| HER2bsFab | HER2-ECD4, FcγRIIIa NK cells, monocytes, macrophages, DCs |
ADCC enhanced HER2 uptake by DCs, TCMC | BsAb linking the pertuzumab Fab to an FcRIIIA single domain Ab In vitro evidence | [101] |
| Ertumaxo Mab |
HER2, CD3, FcγRs NK cells, monocytes, macrophages, DCs |
ADCC enhanced HER2 uptake by DCs, TCMC | Trifunctional bsAb. Phase I trials ORR 30%. Well tolerated, grade 1 flu syndrome | [82,102,103] |
| HER2/CD3 BsAb | CD3 T Cells HER2 |
TCMC | Fc domain silenced to avoid CRS. In vitro evidence | [104] |
| MM-111 | HER2/HER3 heterodimer, HER3 ligand |
AntiHER | bsAb fusion protein. Phase I trial of MM- 111 + trastuzumab or lapatinib. Well tolerated. CBR: 55%. Phase 2 ongoing |
[105,106] |
| BsPD-L1xrErbB2 | HER2, FcγRs, PD-L1/NK cells, monocytes, macrophages, DCs, T cells | ADCC enhanced HER2 uptake by DCs, TCMC | Mouse IgG2a bsAb. In vitro evidence. | [107] |
| HER2Bi-aATCs | HER2 CD3 T cells/macrophages |
TCMC | Mouse IgG2a Fc backbone targeting PD-L1 and rat Her2. Phase I trial CBR: 59.1%, mOS 36,2 | [108] |
| MDX-210 | HER2, FcγRI/monocytes, |
ADCC | Phase I trial. Well tolerated. 10 pts, 1 PR | [109] |
Adapted from Musolino et al. Role of Innate and Adaptive Immunity in the Efficacy of anti-HER2 Monoclonal Antibodies for HER2-positive Breast Cancer. Critical Reviews in Oncology/Hematology (2020), doi: https://doi.org/10.1016/j.critrevonc.2020.102927 [112].
Abbreviations: FcγR, Fc gamma receptor; NK, natural killer, MØ, macrophages; DCs, dendritic cell; ADCC, antibody dependent cell-mediated cytotoxicity; TCMC, T cell-mediated cytotoxicity; BC, breast cancer; Fc, fragment crystallizable; MBC, metastatic breast cancer; ORR, overall response rate; ADC, antibody-drug conjugate; SDR: stable disease rate; w/, with; w/o, without; PFS, progression-free survival; T-DM1, Trastuzumab emtansine; SAE, serious adverse event; ECD, extracellular domain; BsAb, bispecific antibody; DCR: disease control rate (percentage of patients who achieved complete response, partial response, and stable disease to a therapeutic intervention); Fab, fragment antigen-binding; CD16; FcγRIIIa; scFv, single-chain variable fragment; AE, adverse event; BiTE, bispecific T cell engager; IRR, infusion-related reaction; CRS, cytokine release syndrome; p95HER2, truncated form of HER2; SoC, standard of care; CBR, clinical benefit rate (same definition as DCR); HER2Bi-aATCs, activated T cells armed with anti-HER2 bispecific antibody.