Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Blenrep: which risks did reviewers probe?
belantamab mafodotin · BCMA
Immune & cytokine safety
Antibody induced IFN-γ, TNF-α (NK cells) and IL-8 (monocytes) release; ADA/immune complex disease in monkeys
“Other toxicity studies showed GSK2857914 to cause cytokine release, with IFN-γ and TNF-α produced predominantly by the NK cells, and IL-8 by monocytes.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 32Source ↗
Biodistribution & persistence
Rat: ADC in liver, kidney, ocular connective tissue, lacrimal/harderian glands and eyelid muscle
“Belantamab mafodotin could be detected in the liver, kidney, connective tissue of the eyes and eyelids, lacrimal and harderian glands, and muscle of the eyelids in rats.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Modality-specific risk
MMAF-driven corneal toxicity via non-specific (macropinocytosis) uptake; also nephrotoxicity and pro-inflammatory responses
“The data support the involvement of non-specific macropinocytosis as a mechanism of cellular uptake to the eye and indicate that the ocular adverse effects observed in rats result from unspecific uptake leading to microtubulin inhibition and apoptosis due to the cys-mcMMAF moiety.”
Free payload and catabolites (animal PK)
Deconjugated cys-mcMMAF measured in animals: less than 3% of total conjugated MMAF; ADC and antibody levels comparable
“Plasma concentrations were overall comparable between belantamab mafodotin and the antibody, GSK2857914, and there was less than 3% of deconjugated cys-mcMMAF when compared to the total conjugated MMAF.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Anti-drug antibodies: animals
13-week monkey: 21 of 36 ADA-positive, 12 of 36 with circulating immune complexes
“Across all dose levels, 21of 36 monkeys tested positive for ADA, 12 of 36 monkeys were positive for circulating immune complexes CIC”
Anti-drug antibodies: patients
Post-dose ADA in 2/274 participants; no obvious effect on safety, efficacy or PK
“post-belantamab mafodotin antibody responses to date have been both low in incidence (2/274 participants) and with no obvious effects on the safety, efficacy, pharmacokinetics, or pharmacodynamics of belantamab mafodotin.”
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
Zynlonta
loncastuximab tesirine · CD19Pro-inflammatory responses (WBC, fibrinogen, multi-organ inflammation) typical of PBD ADCs; ADA in few monkeys