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
Talvey: which risks did reviewers probe?
talquetamab · GPRC5D x CD3
Immune & cytokine safety
In vitro dose-dependent cytokine release (IL-6, IFN-g, TNF-a etc.); ADAs in 10/12 monkeys reduced exposure
“Antidrug antibodies (ADAs) were observed in 10/12 JNJ-64024701-treated monkeys, and ADA-positive animals exhibited decreased JNJ-64024701 exposure following repeated doses.”
Biodistribution & persistence
No distribution studies; IgG-like, confined mainly to vascular space; monkey half-life 9-12 days
“Traditional distribution studies were not conducted for talquetamab, which is an antibody with a molecular weight of 147 kDa.”
Modality-specific risk
On-target/off-tumor toxicity (GPRC5D in skin, hair follicles, tongue) and T-cell activation/cytokine release
“the purpose of this study was to assess the potential on-target/off-tumor toxicity of a CD3xGPRC5D bsAb.”
Anti-drug antibodies: animals
ADA in 10/12 tool-molecule-treated monkeys, with decreased exposure after repeated doses
“Antidrug antibodies (ADAs) were observed in 10/12 JNJ-64024701-treated monkeys, and ADA-positive animals exhibited decreased JNJ-64024701 exposure following repeated doses.”
Anti-drug antibodies: patients
ADA in 25% (0.4 mg/kg weekly) and 18% (0.8 mg/kg every 2 weeks) of patients
“45/177 (25%) patients treated with subcutaneous TALVEY 0.4 mg/kg weekly (median follow-up 5.7 months) and 24/130 (18%) patients treated with subcutaneous TALVEY 0.8 mg/kg every 2 weeks (median follow-up 3.1 months) developed anti-talquetamab-tgvs 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
Rybrevant
amivantamab · EGFR x METLow CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity
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