Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Emrelis: which risks did reviewers probe?
telisotuzumab vedotin · c-Met
Immune & cytokine safety
No substantial cytokine release from human PBMC; no ADA in 13-week monkey study; low C1q, no complement activation
“In an analysis of cytokine induction in PBMC cultures, telisotuzumab vedotin did not trigger any substantial release of pro-inflammatory cytokines IL-1b, IL-2, IL-6, TNF-α or IFN-γ from human PBMC after 48-hour treatment.”
Biodistribution & persistence
MMAE widely distributed in rat (bile, GI tract, bladder), mainly fecal elimination; ADC target-mediated disposition in monkey
“Radiolabeled MMAE was widely distributed following single IV administration to rats, with highest concentrations in the bile, gastrointestinal (GI) tract, and urinary bladder.”
Modality-specific risk
MMAE payload: myelosuppression, peripheral neuropathy, ocular, GI and reproductive toxicity; aneugenic payload
“Clinically, peripheral neuropathy occurred in 43% of patients. Peripheral neuropathy is a known toxicity of microtubule inhibitors such as MMAE.”
Anti-drug antibodies: animals
No evidence of ADA in 13-week monkey study
“There were no apparent sex differences in exposure or accumulation over the 13-week period and no evidence of anti-drug antibody (ADA) development.”
Anti-drug antibodies: patients
22% (60/269) treatment-emergent ADA; 38% of ADA+ neutralizing
“Following administration of EMRELIS in LUMINOSITY, 22% (60/269) of patients tested positive for treatment-emergent antibodies against telisotuzumab vedotin-tllv at one or more post-baseline time points. Of those who tested positive for anti-drug antibody, neutralizing antibodies were detected in 38% (23/60) 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
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