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
Columvi: which risks did reviewers probe?
glofitamab · CD20 x CD3
Immune & cytokine safety
Marked dose-dependent cytokine release (IL-6 >581-fold); step-up dosing/obinutuzumab mitigated; high ADA incidence limited exposure
“Gpt resulted in the attenuation of cytokine release allowing higher doses to be administered in cynomolgus monkeys. Administration of a low-dose prior to administering higher doses (step-up dosing) also mitigated the dose-limiting cytokine response.”
Biodistribution & persistence
No dedicated distribution studies (ICH S6); TMDD via CD20 with fast clearance in monkeys
“No dedicated studies have been performed to investigate the in vivo tissue distribution of glofitamab in animals, as per ICH S6(R1).”
Modality-specific risk
Cytokine release syndrome (dose-limiting first-dose CRS), mitigated by step-up dosing and obinutuzumab pretreatment
“Three of 7 males in the 0.1 mg/kg group were euthanized on day 1 due to clinical signs associated with cytokine release syndrome.”
Anti-drug antibodies: animals
High ADA incidence in all monkey studies, causing loss of exposure and PD effect; limited study duration to 4 weeks
“In summary, glofitamab was shown to be highly immunogenic in cynomolgus monkeys and to lead to loss of exposure and pharmacological effect in repeat-dose studies. Consequently, no further/longer toxicology studies were conducted, which is accepted.”
Anti-drug antibodies: patients
1.1% (5/448) anti-glofitamab antibodies; neutralizing not reported
“During treatment in Study NP30179 (up to 9 months) [see Clinical Studies (14.1) ] , using an enzyme-linked immunosorbent assay (ELISA), the incidence of anti-glofitamab antibody formation was 1.1% (5/448) in patients treated with COLUMVI.”
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
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
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