Besponsa
inotuzumab ozogamicin · CD22Low ADA incidence in rats (10-13%); no ADA detected in monkeys
Adcetris: which risks did reviewers probe?
brentuximab vedotin · CD30
Immune & cytokine safety
Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”
Biodistribution & persistence
Low Vss for ADC; free MMAE widely distributed (pituitary, adrenal, thyroid, lung, kidney, liver), biliary/fecal excretion; placental transfer
“MMAE was mainly distributed to pituitary gland, adrenal gland, thyroid, lung, kidney, liver and subsequently bile and intestine.”
Modality-specific risk
MMAE payload toxicity: myelotoxicity/neutropenia, testicular toxicity; peripheral neuropathy not reproduced in animals
“Neutropenia and associated mortality was the clinically most significant toxicity observed in non-clinical studies in monkeys.”
Anti-drug antibodies: animals
Monkey anti-drug antibodies (PAHA) reduced ADC and total antibody levels and increased MMAE in high-titre animals
“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”
Anti-drug antibodies: patients
58 ATA-positive patients in phase II studies; 62% of them had neutralizing antibodies
“Of 58 patients with ATA-positive samples, 18 (31%) patients were negative for the presence of neutralizing antibodies, 36 (62%) had at least one sample that was positive for the presence of neutralizing antibodies, and 4 (7%) were of unknown status due to insufficient sample.”
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