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
Lunsumio: which risks did reviewers probe?
mosunetuzumab · CD20 x CD3
Immune & cytokine safety
Dose-dependent cytokine release 2-6 h post-dose; step-up dosing mitigated CRS; high ADA in monkeys; B-cell depletion infections
“Observed toxicities in GLP-study 14-1246 were largely attributed to a dose-dependent release of cytokines which occurred 2-6 hours post-dosing and returned to baseline values at 24 hours post-dose.”
Biodistribution & persistence
Vss above serum volume due to target binding; dose-dependent target-mediated clearance
“Vss-values were greater than estimated serum volume of cynomolgus monkeys, most likely due to specific binding of mosunetuzumab to its target cells.”
Modality-specific risk
First-dose CRS, CNS perivascular inflammation/convulsion, and infections from B-cell depletion
“The main findings were acute toxicities related to cytokine-release syndrome (CRS) primarily attributed to the first dose, vascular/perivascular inflammatory cell infiltrates mainly observed in the CNS and increased susceptibility to infection following chronic dosing.”
Anti-drug antibodies: animals
26-week monkey study: ADA in 5/8 (0.1 mg/kg) and 4/8 (0.5 mg/kg); lower exposure in ADA-positive animals at 0.1 mg/kg only
“ADA was detected in 5 of 8 animals in Group 2 (0.1 mg/kg) and in 4 of 8 animals in Group 3 (0.5 mg/kg) dosed with mosunetuzumab. Exposure appeared to be lower in ADA-positive animals in Group 2 (0.1 mg/kg), while exposure was not consistently impacted in ADA-positive animals in Group 3 (0.5 mg/kg).”
Anti-drug antibodies: patients
No patients (N = 418) developed anti-mosunetuzumab antibodies in Study GO29781
“During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14) ] , using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 418) treated with LUNSUMIO developed anti-mosunetuzumab-axgb 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
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
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