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
Vabysmo: which risks did reviewers probe?
faricimab · VEGF-A x Ang-2
Immune & cytokine safety
ADA-driven immune-complex ocular inflammation in monkey; minimal in vitro cytokine release or complement activation
“These data support that the ocular findings were primarily related to ADA formation and not a direct pro-inflammatory effect of faricimab.”
Biodistribution & persistence
Low systemic bioavailability after IVT (2.2% rabbit, 13% monkey); faster clearance from FcRn-silenced Fc; vitreous cleared after recovery
“Bioavailability was 2.2% in the rabbit and 13% in the cynomolgus monkey.”
Modality-specific risk
Intraocular inflammation/immunogenicity and possible heart findings; anti-angiogenic reproductive risk
“The main adverse findings identified in the nonclinical studies were ocular inflammation and various findings in the heart in both rabbits and monkeys.”
Anti-drug antibodies: animals
ADA in 2- and 6-month monkey studies, correlated with reduced systemic exposure; exposure still sufficient
“A correlation between ADA development and reduced systemic exposure was observed in both 2- and 6-month GLP toxicology studies; this did not compromise the overall readout of the studies because there was still sufficient exposure in ADA-positive animals.”
Anti-drug antibodies: patients
Anti-faricimab antibodies in ~8% to 10.4% of treated patients (0.8-1.8% pre-treatment)
“In the nAMD, DME, and RVO studies, the pre-treatment incidence of anti-faricimab antibodies was approximately 0.8 to 1.8%. After initiation of dosing, the incidence of anti-faricimab antibodies was approximately 8% to 10.4% in patients treated with VABYSMO across studies.”
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
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
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)Low immunogenic potential (PBMC assay); no immunotoxicity in 13-week study; ADA assay drug interference