Which risks did regulators probe for approved ADCs?

“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”

“MMAE was mainly distributed to pituitary gland, adrenal gland, thyroid, lung, kidney, liver and subsequently bile and intestine.”

“In the 4- and 26-week repeat-dose toxicity studies in monkeys, ADA was not detected in any animals after administration of inotuzumab ozogamicin or the G544 antibody.”

“Distribution of [3H]inotuzumab ozogamicin radioequivalents into tissues was limited, with tissue-to-plasma AUCinf ratios ≤0.6 for all tissues evaluated.”

“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.”

“Tissues with the highest concentrations of radioactivity included the small and large intestines, urinary bladder, and kidney.”

“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.”

“The highest concentrations of radioactivity were observed in tissues with high blood volume: bone marrow, liver, kidneys, lungs, heart and spleen.”

“All monkeys administered mirvetuximab soravtansine at doses up to 8 mg/kg/dose tested negative for the presence of anti-drug antibodies (ADAs).”

“The eye:plasma ratio increased through the duration of the study, suggesting that drug clearance from the eyes was slower than from plasma.”

“In an analysis of cytokine induction in PBMC cultures, telisotuzumab vedotin did not trigger any substantial release of pro-inflammatory cytokines IL-1b, IL-2, IL-6, TNF-α or IFN-γ from human PBMC after 48-hour treatment.”

“Radiolabeled MMAE was widely distributed following single IV administration to rats, with highest concentrations in the bile, gastrointestinal (GI) tract, and urinary bladder.”

“In the monkey studies, only pre-dose samples in a few animals in two of the four studies showed detectable ADA (one male in study SBL315-031, 3 animals in Study SBL315-526).”

“After a single administration of 6.4 mg/kg 14C-DS-8201a IV, the highest radioactivity was observed in the large intestinal contents, followed by the blood, lung, adrenal gland, and liver (all tissue-to-blood ratios were less than 1).”

“Blood samples for anti-drug antibody analysis were taken pre-dose and on Day 22. No anti-drug antibodies were detected in the post dose samples.”

“Neither T-DM1 nor free DM1 were associated with tissue persistence or accumulation.”

“Marked eosinophilia occurred at all dose levels and was associated with hypersensitivity reactions in few monkeys dosed with the old cell line.”

“In rats, distribution of [3H]gemtuzumab ozogamicin radioequivalents into red blood cells and tissues was limited, with tissue-to-plasma AUC ratios ≤ 0.54 for all tissues evaluated.”

“Decreases in systemic exposure levels were reported in rats and monkeys following repeat dosing (Day 85 or 22, respectively), due to the presence of anti-drug antibodies (ADAs).”

“Elimination of radioactivity from most tissues was observed at 96 hours post dose, except for the eye uveal tract (t½ = 672 hours post dose), indicating that [ 3H]MMAE likely bound melanin.”

“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.”

“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.”

“Most monkeys developed ADAs following repeated doses of tisotumab vedotin.”

“In cynomolgus monkeys, liver and bone marrow received the highest percent (approx. 20% each) of the injected dose of 89Zr-tisotumab and long persistence were noted.”

“Anti-drug antibodies were detected in all animals at all doses tested in the chronic toxicity study.”

“In addition to tumour, both hRS7 and sacituzumab govitecan distributed to normal tissues, primarily to liver, spleen, kidney and lungs among the normal tissues analysed.”

“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).”

“There was no apparent distribution of SG3199 to melanin‐ containing tissues or the brain or spinal cord.”