How was the first-in-human dose set for approved ADCs?

“The FIH dose of 0.8 mg/kg was selected based on one-twelfth of the human equivalent dose of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys in toxicology studies and was also estimated to provide trough concentration in humans comparable to the minimum effective concentrations in nonclinical studies.”

“The highest non-severely toxic dose of trastuzumab deruxtecan was established at 197 mg/kg in rats (non-binding species), and 30 mg/kg in cynomolgus monkey”

“the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 10 mg/kg for four injections every 3 weeks which was below the no observable adverse effect level in that species and below one-tenth of the severely toxic dose in rats, this information was used to determine a Phase I starting dose in humans.”

“Based on overall tolerability and reversibility of findings, the Applicant considered 10 mg/kg of trastuzumab emtansine given as four injections to Cynomolgus monkeys every 3 weeks to be the highest non-severely toxic dose.”

“MIRV: Dose escalation: 0.15 mg/kg TBW to 7.0 mg/kg TBW (n = 44 Q3W; n = 25 QW)”

“In a 10-week toxicity study in monkeys a mid-dose of 4 mg/kg/dose Q3W of MIRV was selected to characterize potential toxicity at an exposure metric which was predicted to be similar to that of the IV dose (6 mg/kg, AIBW) utilized for the registrational studies. This dose was considered as NOAEL.”

“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation on drug exposure, and the proven utility of 1/6th highest non‐severely toxic dose (HNSTD) for setting clinical starting doses with ADCs.”

“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”

“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”

“Taken together, the primary inotuzumab ozogamicin target organs identified by the chronic toxicity studies were the liver, hematolymphopoietic tissues, and the male and female reproductive organs.”

“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”

“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”

“Myelosuppression occurred at the middle and high doses, which correlated histologically with decreased bone marrow cellularity.”

“The NOAEL was defined at 2.4 mg/m2 /week based on target organ toxicity in the kidney, liver, and lympho-hematopoietic organs at ≥7.2 mg/m2 /week.”

“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”

“The main target organs are bone marrow, lymphoid organs, reproductive organs and liver with less severe effects on eye, skin and pancreas.”

“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”

“In the absence of a NOAEL, the HNSTD in this study was 60 mg/kg/dose.”