Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Kadcyla: which risks did reviewers probe?
ado-trastuzumab emtansine · HER2
Immune & cytokine safety
No ADA detected after single dose in monkey safety pharmacology study; ADA assessed across monkey studies
“Blood samples for anti-drug antibody analysis were taken pre-dose and on Day 22. No anti-drug antibodies were detected in the post dose samples.”
Biodistribution & persistence
Confined largely to plasma; distribution parallels blood flow (lung, kidney, liver); no tissue persistence; predominantly fecal excretion
“Neither T-DM1 nor free DM1 were associated with tissue persistence or accumulation.”
Modality-specific risk
DM1 payload toxicity: hepatotoxicity, thrombocytopenia, peripheral neuropathy (axonal degeneration), pneumonitis
“Increased transaminases and centrilobular vacuolization in monkeys were correlated with hepatic toxicity observed in patients.”
Anti-drug antibodies: animals
No anti-drug antibodies detected post-dose (Day 22) in monkey single-dose safety pharmacology study
“Blood samples for anti-drug antibody analysis were taken pre-dose and on Day 22. No anti-drug antibodies were detected in the post dose samples.”
Anti-drug antibodies: patients
5% (64/1243) ADA-positive; neutralizing in 45% (18/40) of ADA-positive patients
“Among patients who received KADCYLA as a single agent for a median duration of 10 months in seven clinical trials, 5% (64/1243) of patients tested positive for antibodies against ado-trastuzumab emtansine at one or more post-dose timepoints. Neutralizing antibodies against ado-trastuzumab emtansine were detected in 45% (18/40) of evaluable patients who were ADA positive.”
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
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