Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Polivy: which risks did reviewers probe?
polatuzumab vedotin · CD79b
Immune & cytokine safety
Surrogate ADC depleted B cells (expected pharmacology); ADA in monkeys without exposure impact
“Anti-drug-antibodies to polatuzumab vedotin or the surrogate ADC did not appear to impact exposure at any dose level and the toxicokinetic (TK) profiles were similar between ADA-positive and ADA-negative animals.”
Biodistribution & persistence
Rat: non-specific distribution to highly perfused tissues peaking ~2 h; MMAE eliminated >95% in feces
“In a combined distribution and elimination study, MMAE and MMAE-related catabolites of polatuzumab vedotin were primarily eliminated through the hepatobiliary pathway in rats: >95% in feces, ~5% in urine.”
Modality-specific risk
MMAE payload toxicity: myelosuppression, hepatotoxicity, testicular toxicity, genotoxicity; target-mediated B-cell depletion
“Toxicity of polatuzumab vedotin and MMAE observed in rats and Cynomolgus monkeys is consistent with the expected toxicity of a tubulin-binding agent, causing arrest of the cell cycle and apoptosis especially in rapidly dividing tissues.”
Anti-drug antibodies: animals
Monkey ADA 43% (polatuzumab vedotin repeat dose), 20-67% (surrogate ADC); no impact on exposure
“ADA incidence was 67% after a single dose of the surrogate ADC, 20% in Cynomolgus given repeat doses of the surrogate ADC; and 43% in Cynomolgus given repeat-doses of polatuzumab vedotin. Importantly, ADA did not appear to impact the PK/TK of total antibody and unconjugated MMAE exposures.”
Anti-drug antibodies: patients
1.4% (POLARIX) and 6% (GO29365) ADA-positive; none neutralizing
“In studies POLARIX and GO29365, 1.4% (6/427) and 6% (8/134) of patients tested positive for antibodies against polatuzumab vedotin-piiq, respectively, of which none were positive for neutralizing antibodies.”
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
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
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