Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Enhertu: which risks did reviewers probe?
fam-trastuzumab deruxtecan · HER2
Immune & cytokine safety
No treatment-emergent ADA in rat or monkey studies; ADCC activity retained in vitro
“In the monkey studies, only pre-dose samples in a few animals in two of the four studies showed detectable ADA (one male in study SBL315-031, 3 animals in Study SBL315-526).”
Biodistribution & persistence
Monkey 14C-ADC: highest in large intestinal contents, blood, lung, adrenal, liver; minimal CNS; mainly fecal excretion
“After a single administration of 6.4 mg/kg 14C-DS-8201a IV, the highest radioactivity was observed in the large intestinal contents, followed by the blood, lung, adrenal gland, and liver (all tissue-to-blood ratios were less than 1).”
Modality-specific risk
Interstitial lung disease/pulmonary toxicity plus DXd myelo-, intestinal and testicular toxicity; genotoxic payload
“Nevertheless, the presence of HER2 in parenchymal cells of the lung may have an important role in the processes leading to inflammatory changes and interstitial lung toxicity, however, the precise mechanisms are unclear.”
Anti-drug antibodies: animals
No treatment-emergent ADA in rat or monkey studies; only a few pre-dose monkey samples positive
“In the monkey studies, only pre-dose samples in a few animals in two of the four studies showed detectable ADA (one male in study SBL315-031, 3 animals in Study SBL315-526). No other animals were positive for ADA during the studies.”
Anti-drug antibodies: patients
2.2% (49/2,231) developed ADA at 5.4 mg/kg every three weeks (monotherapy)
“Among patients who received ENHERTU as a single agent over a 6 to 9 month treatment period in 13 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 2.2% (49/2,231) of patients who received ENHERTU 5.4 mg/kg every three weeks”
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
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