Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Zynlonta: which risks did reviewers probe?
loncastuximab tesirine · CD19
Immune & cytokine safety
Pro-inflammatory responses (WBC, fibrinogen, multi-organ inflammation) typical of PBD ADCs; ADA in few monkeys
“Treatment of monkeys with loncastuximab tesirine resulted in pro‐inflammatory responses as indicated by increases in the white blood cells (WBCs) and/or differentials, increased fibrinogen, and histopathology observations (multi‐organ inflammation, particularly the lung, kidney, or injection site).”
Biodistribution & persistence
ADC confined to plasma volume, t1/2 8-17 days, stable; [3H]-SG3199 rapid wide distribution, no brain/melanin uptake, biliary excretion
“There was no apparent distribution of SG3199 to melanin‐ containing tissues or the brain or spinal cord.”
Modality-specific risk
PBD payload toxicities: skin hyperpigmentation (photoreactive), myelosuppression, nephropathy, testicular atrophy, effusions/edema, inflammation
“In repeat‐dose toxicity studies in cynomolgus monkeys, loncastuximab tesirine exhibited a safety profile consistent with SG3199‐mediated effects on the skin (epidermal hyperpigmentation with hyperplasia/hyperkeratosis), bone marrow (hypocellularity associated with regenerative anemia)”
Anti-drug antibodies: animals
13-week monkey: ADA in 2 treated animals (Day 85) with notably lower ADC exposure; 5 of 7 positives were pretest
“Note: 5 of the 7 confirmed positive titers were taken from pretest (Day ‐6) samples and 2 of the 7 were from animals on Day 85 (one female each at 0.075 and 0.15 mg/kg). The exposure to conjugated ADCT‐402 was notably lower compared to the profiles of other animals in the respective dosing groups”
Anti-drug antibodies: patients
0 of 134 patients ADA-positive (LOTIS-2)
“In LOTIS-2, 0 of 134 patients tested positive for antibodies against loncastuximab tesirine-lpyl after treatment.”
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
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