Clinical relevance of ADAs to selected BsAbs in oncology
| BsAbs MOA | Molecule | Platform | Targets | Indication | Dosing | ADA incidence | Effects on PK/efficacy | Effects on adverse events | Reference |
| Immune cell engagers/enhancers | Blincyto® (blinatumomab) Approved | BiTE® | CD19, CD3 | BCP ALL | cIV (step dosing): 9–28 µg/day for pts ≥45 kg, 5–15 µg/m2/day for pts <45 kg | <2%, most Nab+ | – | No | 8 |
| Removab® (catumaxomab) Approved, off-market | TrioMab® | EpCAM, CD3 | MA | Intraperitoneal (step-dosing): 10–150 µg/d | HAMA 94% | ND | No | 1 17 18 92 | |
| Kimmtrak® (tebentafusp-tebn) Approved | ImmTAC® | gp100, TCR/CD3 | (HLA-A*02:01+) mUM | Short IV (step-dosing): 20–68 µg QW | TE-ADA 29%–33% | Yes | No | 16 | |
| Pasotuxizumab (AMG 212) Phase I, discontinued | BiTE® | PSMA, CD3 | mCRPC | Subcutaneous: 0.5–172 µg/d; cIV: 5–80 µg/d | Subcutaneous: 97% (30/31), most Nab+ (28/30) cIV: 0% (0/16) | Yes | No | NCT0172347513 | |
| AMG 211 (MEDI-565) Phase I, discontinued | BiTE® | CEA, CD3 | GI AdCA | cIV: 200–12800 µg/d | cIV: 100% at dose cohorts>3200 µg/d | Yes | No | NCT0229161412 | |
| APVO-414 (MOR209/ES414) Phase I, discontinued | ADAPTIRTM | PSMA, CD3 | mCRPC | Short IV QW: 0.2–2 µg/kg cIV: 25–300 µg/day | Short IV: 58% with very high titers cIV: 50% with markedly lower titer | Yes | No | NCT0226291014 62 74 93 94 | |
| JNJ-081 (JNJ-63898081) Phase I, discontinued | DuoBody® | PSMA, CD3 | mCRPC | IV QW: 0.1–3 µg/kg Subcutaneous QW: 3–60 µg/kg, with or without step-dosing | IV QW: 16.7% (2/12) Subcutaneous QW: 63.0% (17/27) | Yes | ND | NCT0392601315 | |
| Glofitamab (RG6026/RO7082859) Phase III | CrossMab/KIH/TCB (2+1) | CD20, CD3 | B-NHL | Phase I study (NCT03075696) Short IV: 0.005–30 mg (including 2.5-10-30 mg step-dosing as RP2D) | 0% | – | – | NCT030756969 | |
| Elranatamab (PF 06863135) Phase III | Fab+Fab+Fc, 1+1 | BCMA, CD3 | MM | MagnetisMM-1 (Phase I study; NCT03269136) Dose escalation (Part 1, n=30: 80 to 1000 µg/kg QW subcutaneous); Priming cohort (Part 1.1, n=20; step-dosing: 600–1000 µg/kg QW or Q2W); Expansion (Part 2A, n=15; step-dosing: 44–76 mg QW) | Dose escalation (Part 1):10.7% | No | – | MagnetisMM-1 NCT0326913610 95 | |
| Teclistamab (JNJ-64007957) Phase III | DuoBody® | BCMA, CD3 | MM | MajesTEC-1 (Phase I/II study; NCT03145181; NCT04557098) RP2D including step doses of 0.06 and 0.3 mg/kg subcutaneous during week 1, followed by 1.5 mg/kg target dosing QW subcutaneous | RP2D: 0% (0/146) developing ADA 0.46% (1/219) developing ADA with low titer from 0.24 mg/kg subcutaneous QC dose level | – | – | MajesTEC-1 NCT03145181; NCT0455709811 | |
| ABBV-383 (TNB-383B) Phase I | Fab+SDA with Fc, 1+2 | BCMA, CD3 | MM | Phase I FIH study (NCT03933735) IV Q3W: range 0.025–120 mg including RP2D of 60 mg IV Q3W | 5.3% (4/76) from IV Q3W cohorts with dose ≥40 mg | – | – | NCT0393373596 | |
| Talquetamab (JNJ-64407564) Phase II | DuoBody® | GPRC5D, CD3 | MM | MonumenTAL-1 (Phase I FIH study; NCT03399799) IV QW or Q2W: range 0.5–180 µg/kg subcutaneous QW or Q2W: range 5.0–800 µg/kg, including RP2D of step dosing followed by 405 µg/kg subcutaneous QW or 800 µg/kg subcutaneous Q2W | 11% (7/61) developed ADA from subcutaneous cohorts, generally of low titer | No | No | MonumenTAL-1 NCT0339979997 | |
| AFM13 Phase II, registrational | TandAb | CD30/CD16A | HL, T-cell lymphoma | Phase I FIH study (NCT01221571) Short IV QW: 0.01–7 mg/kg Phase Ib study (NCT02665650) Step dosing 0.1–0.5; 0.5–1.5; 3.0–7.0 mg/kg | Phase I FIH (NCT01221571) 53.6% (15/28); half (8/15) Nab+ Phase Ib study (NCT02665650) 56.7% (17/30) | - No | - - | NCT01221571; NCT0266565062 98–100 | |
| ABBV-428 Phase I | (scFv)2+(scFv)2+Fc, 2+2 | CD40/MSLN | Solid tumors | Short IV Q2W: 0.01–3.6 mg/kg (3.6 mg/kg as RP2D) | 63% | Yes PK impact at dose ≤0.80 mg/kg | – | NCT02955251101 | |
| Cinrebafusp Alfa (PRS-343) Phase I/II | Anticalin® | HER2, 4-1BB | (HER2+) solid tumors | Phase 1 FIH study (NCT03330561) Short intravenous: 0.0005–8.0 mg/kg | 27.8% with titers above 1:150 at dose ≥2.5 mg/kg | – | – | NCT0333056162 68 | |
| Blocking of dual TAAs/signal pathways | Rybrevant® (amivantamab) Approved | DuoBody® | EGFR, C-MET | (EGFRm) NSCLC | Short intravenous step dosing: 350–1400 mg for pts ≥80 kg, 350–1050 mg for pts <80 kg | 1% (3/286) | – | – | US PI 2021 |
| Vanucizumab (RO5520985/RG-7221) Phase II, discontinuted | CrossMab | VEGF-A, ANG-2 | Solid tumors | Phase I FIH study (NCT01688206) IV 3–30 mg/kg Q2W or 10–30 mg/kg QW Phase II study (NCT02141295) IV: 2000 mg Q2W | Phase I FIH study (NCT01688206) two developing (5%) and two pe-existing Phase II study (NCT02141295) three developing and four pre-exiting | No – | No – | NCT01688206 NCT02141295102 103 | |
| Navicixizumab (OMP-305B83) Phase I | XernaTM | DLL4/VEGF | Solid tumors | Phase I FIH study (NCT02298387) Short IV Q3W: 0.5–12.5 mg/kg Phase Ib study (NCT03030287) Three or 4 mg/kg | Phase I FIH study (NCT02298387) 29% (19/65) Majority from low-dose groups of ≤2.5 mg/kg (56%; 10/18) Phase Ib study (NCT03030287) 16% (4/25) | Yes Yes | – Yes | NCT02298387 NCT0303028719 104 | |
| Blocking of immune checkpoints | LY3415244 Phase I, discontinued | NA | PD-L1, TIM-3 | Solid tumors | Phase I FIH study (NCT03752177) Short IV Q2W: 3–70 mg | TE-ADA 100% | Yes | – | NCT0375217735 41 |
| FS118 Phase I/II | IgG with Fcab, 2+2 mAb2 | PD-L1, LAG3 | Advanced malignancies | Phase I FIH study (NCT03440437) Short IV QW: 0.8–20 mg/kg | 42% (low titer; transient at higher dose levels) | No | – | NCT0344043762 63 |
−, not determined or insufficient data to evaluate ADA effect; ADA, anti-drug antibody; AMG, Amgen identification number; ANG-2, angiogenic factor angiopoetin-2; BCMA, B-cell maturation antigen; BCP-ALL, B-cell precursor acute lymphoblastic leukemia; BiTE, bispecific T-cell engager; B-NHL, B-cell non-Hodgkin's lymphoma; BsAb, bispecific antibody; CEA, carcinoembryonic antigen; cIV, continuous intravenous infusion; C-MET, mesenchymal–epithelial transition tyrosine kinase receptor; DLL4, delta-like ligand 4; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell-adhesion molecule; FIH, first-in-human; GI AdCA, gastrointestinal adenocarcinoma; GPRC5D, G protein-coupled receptor family C group 5 member D; HAMA, human anti-murine antibody; HER2, human epidermal growth factor receptor 2; HL, Hodgkin’s lymphoma; ImmTAC, immune mobilizing monoclonal TCRs against cancer; KIH, knobs-into-holes; MA, malignant ascites; mCRPC, metastatic castration-resistant prostate cancer; MM, multiple myeloma; MOA, mechanism of action; MSLN, mesothelin; mUM, metastatic uveal melanoma; NCT, clinicaltrials.gov National Clinical Trials identification number; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; PI, product information; PSMA, prostate-specific membrane antigen; pts, patients; RP2D, recommended phase II dose; SDA, single domain antibody; TandAb, tetravalent tandem diabody; TCB, tethered-variable CL bispecific IgG; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin domain-containing molecule 3; TrioMab, trifunctional antibody; VEGF, vascular endothelial growth factor.