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Atlas/Bispecific antibodies/Talvey/Risks

Talvey: which risks did reviewers probe?

talquetamab · GPRC5D x CD3
Check my plan vs. these
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.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗
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.”
✓ VerifiedEMA assessment report, p. 42Source ↗
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.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Same question, other bispecifics

Bizengri

zenocutuzumab · HER2 x HER3
Low 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

Blincyto

blinatumomab · CD19 x CD3
IL-2, IL-6, IFN-gamma release in chimpanzees, consistent with clinical CRS; ADA to surrogate in mice

Columvi

glofitamab · CD20 x CD3
Marked dose-dependent cytokine release (IL-6 >581-fold); step-up dosing/obinutuzumab mitigated; high ADA incidence limited exposure

Elrexfio

elranatamab · BCMA x CD3
Transient cytokine increases mainly after first dose; B-cell/plasma cell depletion; ADA incidence up to 67% at low dose

Epkinly

epcoritamab · CD20 x CD3
Dose-dependent first-dose cytokine release (lower with SC); strong neutralizing ADA at ≤0.1 mg/kg IV

Hemlibra

emicizumab · FIXa x FX
Low cytokine release risk in vitro; ADA in 9/40 monkeys (4 NAb); one Arthus-type injection-site reaction

Imdelltra

tarlatamab · DLL3 x CD3
Inflammatory 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 CD3
In vitro TNF-α/IL-6/IL-2 release with EpCAM+ cells; transient lymphopenia (BiLu); neutralising HAMA/HARA

Lunsumio

mosunetuzumab · CD20 x CD3
Dose-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 CD3
Transient 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 CD3
Transient T-cell activation and plasma cytokine rise after first dose only; limited translatability of in vitro cytokine data to CRS

Removab

catumaxomab · EpCAM x CD3
In vitro TNF-α, IL-6, IL-2 release (needs EpCAM+ cells); no cytokine change in monkey; anti-mouse/rat ADA

Rybrevant

amivantamab · EGFR x MET
Low CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity

Tecvayli

teclistamab · BCMA x CD3
ADA 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-2
ADA-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

Summary across all 18 bispecifics →