Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Padcev: which risks did reviewers probe?
enfortumab vedotin · Nectin-4
Immune & cytokine safety
ADA in rats and monkeys reduced exposure on repeat dosing; no ADCC/CDC, ADCP activity in vitro
“Decreases in systemic exposure levels were reported in rats and monkeys following repeat dosing (Day 85 or 22, respectively), due to the presence of anti-drug antibodies (ADAs).”
Biodistribution & persistence
Rat [3H]MMAE QWBA: wide distribution, bile/bladder highest; prolonged uveal retention (melanin binding); fecal excretion
“Elimination of radioactivity from most tissues was observed at 96 hours post dose, except for the eye uveal tract (t½ = 672 hours post dose), indicating that [ 3H]MMAE likely bound melanin.”
Modality-specific risk
On-target skin and eye toxicity (Nectin-4 expression) plus MMAE myelosuppression, liver, neuropathy, hyperglycemia
“The eye and skin were identified in tissue cross reactivity studies in human and/or monkey (skin) as Nectin-4 expressing tissues, as such they were considered target-mediated toxicities.”
Anti-drug antibodies: animals
ADA in rats and monkeys decreased exposure on repeat dosing (Day 85 rat, Day 22 monkey)
“Decreases in systemic exposure levels were reported in rats and monkeys following repeat dosing (Day 85 or 22, respectively), due to the presence of anti-drug antibodies (ADAs).”
Anti-drug antibodies: patients
3.7% (25/684) single agent; 1.3% and 7% with pembrolizumab; effect unknown
“Anti‑enfortumab vedotin-ejfv antibodies developed in: • 3.7% (25/684) of patients who received PADCEV as a single agent. • 1.3% (2/156) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC. • 7% (34/485) of patients”
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
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