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
Korjuny: which risks did reviewers probe?
catumaxomab · EpCAM x CD3
Immune & cytokine safety
In vitro TNF-α/IL-6/IL-2 release with EpCAM+ cells; transient lymphopenia (BiLu); neutralising HAMA/HARA
“In vitro data show that catumaxomab can induce the production of pro-inflammatory cytokines (e.g. TNF-α, IL-6 and IL-2) in the presence of EpCAM-expressing tumour cells.”
Biodistribution & persistence
123I-catumaxomab SCID xenograft: tumour peak 15.7% ID/g at 48 h; i.p. bioavailability 82%; mouse t1/2 128 h
“Tumour uptake of catumaxomab increased over the first 48 h and peaked at 15.7% ID/g; it then declined to 6.6% ID/g on Day 4.”
Modality-specific risk
Cytokine release and transient lymphopenia; liver (BiLu); on-target normal EpCAM tissue untestable; murine ADA
“Potential risks associated with the use of catumaxomab were identified in secondary PD studies, i.e. cytokine release that is enhanced in the presence of EpCAM-positive tumour cells and transient lymphopenia.”
Anti-drug antibodies: animals
Single cynomolgus monkey developed antibodies against mouse and rat Ig one week after last dose; TK not evaluated
“TK was not evaluated as part of the study, although the development of ADA was assessed. One week after the last dose, antibodies against mouse Ig and rat Ig were detected.”
Anti-drug antibodies: patients
90-100% of patients ADA-positive 28-30 days after the last infusion
“At 28 to 30 days after the last infusion, 90-100% of patients were ADA positive across the 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
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