Bizengri
zenocutuzumab · HER2 x HER3Low whole-blood cytokine release; cytokine release (IFN-g, IL-6, IL-8, TNF-a) when target and effector cells co-cultured; ADA in ~1/3 of monkeys
Rybrevant: which risks did reviewers probe?
amivantamab · EGFR x MET
Immune & cytokine safety
Low CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity
“In an in vitro assay using human blood, the cytokine release profile for amivantamab was similar to that of the negative control, indicating a low risk for cytokine release syndrome.”
Biodistribution & persistence
No distribution/metabolism/excretion studies (IgG mAb); nonlinear TMDD PK below 20 mg/kg/week
“Conventional distribution, metabolism, and excretion studies were not conducted for amivantamab since it is a immunoglobulin G (IgG)-based monoclonal antibody (mAb) with a molecular weight of approximately 148,000 Daltons (kD).”
Modality-specific risk
On-target EGFR/MET epithelial toxicity under-tested: only ~5x margin and lower cyno potency; embryofetal risk
“However, the exposure margin at the highest dose was only about 5-fold the clinical AUC indicating that the high dose levels were not set at an appropriate level.”
Anti-drug antibodies: animals
17 of 67 monkeys ADA-positive; 5 of these showed faster concentration decrease
“Among the 67 cynomolgus monkeys dosed with amivantamab in the IV single-dose, 1-month, 6-week, and 3-month studies, 17 tested positive for the presence of anti-drug antibodies (ADA). Five of the 17 ADA-positive animals exhibited a faster concentration decrease compared with other animals in the same dose group.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 0.2% (4/1,862) of patients
“4 of the 1,862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies.”
Same question, other multispecifics
Blincyto
blinatumomab · CD19 x CD3IL-2, IL-6, IFN-gamma release in chimpanzees, consistent with clinical CRS; ADA to surrogate in mice
Columvi
glofitamab · CD20 x CD3Marked dose-dependent cytokine release (IL-6 >581-fold); step-up dosing/obinutuzumab mitigated; high ADA incidence limited exposure
Elrexfio
elranatamab · BCMA x CD3Transient cytokine increases mainly after first dose; B-cell/plasma cell depletion; ADA incidence up to 67% at low dose
Epkinly
epcoritamab · CD20 x CD3Dose-dependent first-dose cytokine release (lower with SC); strong neutralizing ADA at ≤0.1 mg/kg IV
Hemlibra
emicizumab · FIXa x FXLow cytokine release risk in vitro; ADA in 9/40 monkeys (4 NAb); one Arthus-type injection-site reaction
Imdelltra
tarlatamab · DLL3 x CD3Inflammatory markers (CRP, MCP-1, IFNg) in 10-day study; dose-related ADAs, one ADA immune-complex vascular injury case
Kimmtrak
tebentafusp · CD3 x gp100 (TCR fusion)Whole-blood assays: no cytokine increase <1 nM; IL-6, TNFa, IFNg at 10-100 nM; no alloreactivity or platelet activation
Korjuny
catumaxomab · EpCAM x CD3In vitro TNF-α/IL-6/IL-2 release with EpCAM+ cells; transient lymphopenia (BiLu); neutralising HAMA/HARA
Lunsumio
mosunetuzumab · CD20 x CD3Dose-dependent cytokine release 2-6 h post-dose; step-up dosing mitigated CRS; high ADA in monkeys; B-cell depletion infections
Lynozyfic
linvoseltamab · BCMA x CD3Transient emesis with CRP/cytokine increase; sustained CRP, IL-2, IL-6, MCP-1 inflammation; ADA in 36-47% of monkeys reduced exposure
Ordspono
odronextamab · CD20 x CD3Transient T-cell activation and plasma cytokine rise after first dose only; limited translatability of in vitro cytokine data to CRS
Removab
catumaxomab · EpCAM x CD3In vitro TNF-α, IL-6, IL-2 release (needs EpCAM+ cells); no cytokine change in monkey; anti-mouse/rat ADA
Talvey
talquetamab · GPRC5D x CD3In vitro dose-dependent cytokine release (IL-6, IFN-g, TNF-a etc.); ADAs in 10/12 monkeys reduced exposure
Tecvayli
teclistamab · BCMA x CD3ADA in 21/30 monkeys (7 with reduced exposure); in vitro whole-blood cytokine release of IL-8, IFN-γ, TNF-α
Vabysmo
faricimab · VEGF-A x Ang-2ADA-driven immune-complex ocular inflammation in monkey; minimal in vitro cytokine release or complement activation
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)Low immunogenic potential (PBMC assay); no immunotoxicity in 13-week study; ADA assay drug interference