Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Tivdak: which risks did reviewers probe?
tisotumab vedotin · Tissue factor
Immune & cytokine safety
ADA in most monkeys after repeat dosing, reduced exposure in some; immunotoxic potential minimal
“Most monkeys developed ADAs following repeated doses of tisotumab vedotin.”
Biodistribution & persistence
Monkey 89Zr-PET: highest uptake liver and bone marrow (~20% each); MMAE fecal elimination
“In cynomolgus monkeys, liver and bone marrow received the highest percent (approx. 20% each) of the injected dose of 89Zr-tisotumab and long persistence were noted.”
Modality-specific risk
Target-mediated skin and ocular toxicity plus MMAE myelosuppression, testicular toxicity; bleeding (TF/coagulation)
“Skin and ocular toxicities could be expected from the TF-directed antibody portion of tisotumab vedotin as tisotumab was shown to positively stain skin epithelial cells (squamous epidermis, hair follicle), and corneal and conjunctiva epithelial cells, in both human and monkey in a tissue cross reactivity study.”
Anti-drug antibodies: animals
Monkey ADA after repeat dosing, mainly at 5 mg/kg; no apparent effect on Cmax or total exposure
“After repeated dosing, animals developed anti-drug antibodies (ADA) especially at the high dose of 5 mg/kg, but ADA did not appear to affect the peak plasma concentration or total exposure.”
Anti-drug antibodies: patients
5.7% (innovaTV 301) and 5.4% (innovaTV 204); neutralizing 0% and 2.2%
“the incidence of anti-tisotumab vedotin-tftv antibody formation was 5.7% (12/211) and 5.4% (5/93), respectively. The incidence of neutralizing anti-tisotumab vedotin-tftv antibody formation was 0% (0/211) in innovaTV 301 using cell-based assay, and the incidence was 2.2% (2/93) in innovaTV 204 using Enzyme-linked Immunosorbent Assay (ELISA)-based assay.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Low ADA incidence in rats (10-13%); no ADA detected in monkeys
Datroway
datopotamab deruxtecan · Trop-2ADA in 5/6 monkeys at 10 mg/kg reducing exposure; minimal in vitro cytokine release; transient CRP increases
Decnupaz
pivekimab sunirine · CD123ADA in monkeys reduced exposure; thymic lymphoid depletion and lymphopenia; ADCC present in vitro
Elahere
mirvetuximab soravtansine · FRαNo ADA in any monkey up to 8 mg/kg; bone marrow and lymphoid depletion; no stand-alone immunotox
Emrelis
telisotuzumab vedotin · c-MetNo substantial cytokine release from human PBMC; no ADA in 13-week monkey study; low C1q, no complement activation
Enhertu
fam-trastuzumab deruxtecan · HER2No treatment-emergent ADA in rat or monkey studies; ADCC activity retained in vitro
Kadcyla
ado-trastuzumab emtansine · HER2No ADA detected after single dose in monkey safety pharmacology study; ADA assessed across monkey studies
Mylotarg
gemtuzumab ozogamicin · CD33ADA in rats (reduced exposure) and some monkeys; marked eosinophilia and hypersensitivity reactions in monkeys
Padcev
enfortumab vedotin · Nectin-4ADA in rats and monkeys reduced exposure on repeat dosing; no ADCC/CDC, ADCP activity in vitro
Polivy
polatuzumab vedotin · CD79bSurrogate ADC depleted B cells (expected pharmacology); ADA in monkeys without exposure impact
Trodelvy
sacituzumab govitecan · Trop-2ADA in all monkeys at all doses in 13-week study, reducing low-dose exposure; reduced thymic/lymphoid cellularity
Zynlonta
loncastuximab tesirine · CD19Pro-inflammatory responses (WBC, fibrinogen, multi-organ inflammation) typical of PBD ADCs; ADA in few monkeys