Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Elahere: which risks did reviewers probe?
mirvetuximab soravtansine · FRα
Immune & cytokine safety
No ADA in any monkey up to 8 mg/kg; bone marrow and lymphoid depletion; no stand-alone immunotox
“All monkeys administered mirvetuximab soravtansine at doses up to 8 mg/kg/dose tested negative for the presence of anti-drug antibodies (ADAs).”
Biodistribution & persistence
Rat radiolabel: liver, bone marrow, lung, kidney, spleen highest; slow ocular clearance; testis penetration; brain <3%; fecal elimination
“The eye:plasma ratio increased through the duration of the study, suggesting that drug clearance from the eyes was slower than from plasma.”
Modality-specific risk
DM4 payload ocular toxicity (corneal degeneration/keratopathy) plus myelosuppression and skin toxicity; dedicated rabbit ocular studies
“Due to ocular toxicities observed in both animal toxicity studies and in patients, the Applicant also conducted GLP compliant repeated-dose toxicity studies to evaluate ocular toxicity of mirvetuximab soravtansine in male rabbits.”
Anti-drug antibodies: animals
No ADA in any monkey at doses up to 8 mg/kg
“All monkeys administered mirvetuximab soravtansine at doses up to 8 mg/kg/dose tested negative for the presence of anti-drug antibodies (ADAs).”
Anti-drug antibodies: patients
9% (57/626) developed ADA at 6 mg/kg AIBW Q3W
“In studies 0416, 0417, 0401, and 0403 in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received ELAHERE at 6 mg/kg AIBW administered intravenously once every 3 weeks, 9% (57/626) developed anti-drug antibodies.”
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
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
Tivdak
tisotumab vedotin · Tissue factorADA in most monkeys after repeat dosing, reduced exposure in some; immunotoxic potential minimal
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