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
Imdelltra: which risks did reviewers probe?
tarlatamab · DLL3 x CD3
Immune & cytokine safety
Inflammatory markers (CRP, MCP-1, IFNg) in 10-day study; dose-related ADAs, one ADA immune-complex vascular injury case
“One animal had vascular injury-associated changes in the heart and lung that were consistent with secondary effects likely mediated by ADA-related immune complexes.”
Biodistribution & persistence
Tarlatamab detected in monkey CSF at ~0.05% of serum; surrogate fetal serum up to 30x maternal
“muS757 was detected in fetal serum at concentrations up to 30-times higher than maternal serum concentrations, indicating the potential for tarlatamab to cross the placenta.”
Modality-specific risk
T-cell activation/cytokine release and on-target DLL3 tissue effects (pituitary infiltrates; DLL3 intracellular in brain/pituitary)
“At doses ≥50 µg/kg, minimal to mild mononuclear cell infiltrates were noted in the pituitary gland of monkeys”
Anti-drug antibodies: animals
Dose-related ADA incidence in monkeys, adding exposure variability; one ADA immune-complex vascular injury
“A dose-related increase in incidence of antidrug antibodies (ADAs) occurred, which potentially contributed to variability in exposure levels at the end of the study. One animal had vascular injury-associated changes in the heart and lung that were consistent with secondary effects likely mediated by ADA-related immune complexes.”
Anti-drug antibodies: patients
8% (36/445) treatment-emergent ADA; 38% (11/29) of ADA-positive patients neutralizing
“8% (36/445) of patients who received the recommended step-up and full dose of IMDELLTRA developed treatmentemergent ADA. In DeLLphi-301 and DeLLphi-304, which included neutralizing antibody assessments, 38% (11/29) of the patients who developed treatment-emergent ADA also developed neutralizing 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
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