Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Besponsa: which risks did reviewers probe?
inotuzumab ozogamicin · CD22
Immune & cytokine safety
Low ADA incidence in rats (10-13%); no ADA detected in monkeys
“In the 4- and 26-week repeat-dose toxicity studies in monkeys, ADA was not detected in any animals after administration of inotuzumab ozogamicin or the G544 antibody.”
Biodistribution & persistence
Limited tissue distribution in rat (tissue:plasma <=0.6; liver highest), minimal brain penetration, longer tissue retention
“Distribution of [3H]inotuzumab ozogamicin radioequivalents into tissues was limited, with tissue-to-plasma AUCinf ratios ≤0.6 for all tissues evaluated.”
Modality-specific risk
Calicheamicin payload: hepatic sinusoidal endothelial injury (VOD precursor), thrombocytopenia, genotoxicity, reproductive toxicity
“consistent with microvascular liver injury and were considered to represent the early stages of veno-occlusive disease that has been reported in clinical trials.”
Anti-drug antibodies: animals
No ADA detected in monkeys in 4- and 26-week studies
“In the 4- and 26-week repeat-dose toxicity studies in monkeys, ADA was not detected in any animals after administration of inotuzumab ozogamicin or the G544 antibody.”
Anti-drug antibodies: patients
3% (7/236) ADA-positive in relapsed or refractory ALL; no neutralizing antibodies
“During a maximum 6 cycles of treatment period in clinical studies of BESPONSA in adult patients with relapsed or refractory ALL, 7/236 (3%) patients tested positive for ADA. No patients tested positive for NAb.”
Same question, other ADCs
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
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