Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Decnupaz: which risks did reviewers probe?
pivekimab sunirine · CD123
Immune & cytokine safety
ADA in monkeys reduced exposure; thymic lymphoid depletion and lymphopenia; ADCC present in vitro
“In animals that were ADA positive, there was a noticeable decrease in systemic exposure to both PVEK and TAb on Day 85 vs Day 1.”
Biodistribution & persistence
[3H]PVEK in rat: highest in marrow, liver, kidney, lung, heart, spleen; tissue:plasma <1; mainly fecal/biliary excretion
“The highest concentrations of radioactivity were observed in tissues with high blood volume: bone marrow, liver, kidneys, lungs, heart and spleen.”
Modality-specific risk
DNA-alkylating IGN payload: myelosuppression, GI, skin, liver/VOD; genotoxic payload
“Most notably from the nonclinical studies, bone marrow depletion, gastrointestinal toxicity, and elevated liver enzymes corresponded directly to the most significant clinical adverse events requiring management through dose modifications and supportive care, including veno-occlusive disease (VOD).”
Anti-drug antibodies: animals
ADA-positive monkeys had decreased ADC and total antibody exposure on Day 85 vs Day 1
“In animals that were ADA positive, there was a noticeable decrease in systemic exposure to both PVEK and TAb on Day 85 vs Day 1.”
Anti-drug antibodies: patients
24% (19/80) BPDCN patients ADA-positive; neutralizing in 78% (14/18) of evaluable ADA-positive patients
“Following administration of pivekimab sunirine-pvzy in CADENZA in BPDCN patients, 19/80 (24%) of patients tested positive for treatment emergent antibodies against pivekimab sunirine-pvzy. Of those who tested positive for anti-drug antibody, neutralizing antibodies were detected in 14/18 (78%) of evaluable 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
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