Adcetris
brentuximab vedotin · CD30Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
Datroway: which risks did reviewers probe?
datopotamab deruxtecan · Trop-2
Immune & cytokine safety
ADA in 5/6 monkeys at 10 mg/kg reducing exposure; minimal in vitro cytokine release; transient CRP increases
“Five of 6 monkeys given 10 mg/kg showed ADA positive responses after the 3-month dosing period, and there was a reduction in Dato-DXd exposure after the 4th dose compared to the 1st dose.”
Biodistribution & persistence
14C-DXd rapid wide distribution without retention (highest intestine, bladder, kidney); low DXd release in plasma (≤6.5%); biliary/fecal excretion
“Tissues with the highest concentrations of radioactivity included the small and large intestines, urinary bladder, and kidney.”
Modality-specific risk
Interstitial lung disease (Trop2 in alveolar epithelium), ocular surface/corneal toxicity, GI and hematologic DXd payload toxicity
“Lung toxicity noted in monkeys is consistent with expression of Trop2 in the lung, and Trop2 staining was noted on the plasma membrane of the alveolar epithelium in humans and monkeys with similar frequency and intensity in a tissue-cross reactivity study.”
Anti-drug antibodies: animals
ADA in 5 of 6 monkeys at 10 mg/kg, reducing ADC exposure after the 4th dose
“Five of 6 monkeys given 10 mg/kg showed ADA positive responses after the 3-month dosing period, and there was a reduction in Dato-DXd exposure after the 4th dose compared to the 1st dose.”
Anti-drug antibodies: patients
17% (223/1333) ADA-positive; 17% of these neutralizing
“During the median 5.8-month treatment period across 6 clinical studies in patients with NSCLC or breast cancer who received DATROWAY 6 mg/kg once every 3 weeks, 17% (223 out of 1333) of patients developed anti-datopotamab deruxtecan-dlnk antibodies with 17% (37 out of 223) of these patients developing neutralizing antibodies against datopotamab deruxtecan-dlnk.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Low ADA incidence in rats (10-13%); no ADA detected in monkeys
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