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
Kimmtrak: which risks did reviewers probe?
tebentafusp · CD3 x gp100 (TCR fusion)
Immune & cytokine safety
Whole-blood assays: no cytokine increase <1 nM; IL-6, TNFa, IFNg at 10-100 nM; no alloreactivity or platelet activation
“Tebentafusp did not show evidence for increased release of 5 key cytokines in the presence of whole blood at < 1 nM.”
Biodistribution & persistence
Mouse non-GLP PK/biodistribution: tumor retention longer than other tissues (tumor t1/2 ~20-24 h vs blood 1.5 h); renal excretion
“Preclinical biodistribution studies demonstrate that tebentafusp is being retained in the melanoma tumor for a significantly longer timeframe compared to other non-target tissues, with a half-life of tumour retention of approximately 24 hours.”
Modality-specific risk
On-target/off-tumor melanocyte killing (rash, vitiligo) and CRS; HLA/peptide off-target cross-reactivity and alloreactivity
“Based on these [astrocyte and melanocyte] data, skin rash and potentially vitiligo were expected as the primary TCR mediated on‐target, off‐tumor toxicities.”
Anti-drug antibodies: animals
Not analysed; higher clearance and lower AUC after 5-day repeat dosing in mice possibly due to ADAs
“It should be mentioned that clearance was higher and AUC was lower after 5 days of repeat dosing and this was by the applicant attributed to possibly be due to ADAs, which however was not analysed for in this study (IM-CH-01-10).”
Anti-drug antibodies: patients
ADA in 36% (47/131, IMCgp100-102) and 28% (67/240, IMCgp100-202) of patients
“In studies IMCgp100-102 and IMCgp100-202, 36% (47/131) and 28% (67/240) of patients who were treated with tebentafusp-tebn at the recommended dosing regimen for up to 29 cycles and 45 cycles, respectively, developed anti-tebentafusp-tebn antibodies (ADA).”
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
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