Which animal species did regulators accept for approved ADCs?

“Single- and repeat-dose toxicology studies were conducted in rats and monkeys. The pivotal repeat-dose toxicity studies were GLP compliant.”

“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”

“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”

“G544 did not bind B cells from mouse, rat, rabbit, or cynomolgus monkey whole blood, or granulocytes, MONO, or T cells from any species evaluated, including humans.”

“Though datopotamab deruxtecan did not bind rat Trop2 in an in vitro assay, the monkey is a pharmacologically relevant species considering datopotamab deruxtecan demonstrated similar binding to human and monkey Trop2.”

“Datopotamab deruxtecan bound to human and monkey Trop2 similarly in an ELISA-based assay but demonstrated weak to no binding to mouse and rat Trop2.”

“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”

“PVEK produced less intense and less frequently observed staining in monkey mononuclear cells.”

“The monkey was demonstrated to be the most appropriate animal species for toxicological evaluation of MIRV based on FOLR1 gene sequence homology assessments, in vitro binding assays, and IHC analysis of FRα protein expression on fresh frozen tissue sections using MIRV.”

“MIRV (and M9346A) cross-reacts only with rhesus and cynomolgus monkey FRα, out of toxicological species.”

“In addition, these studies support the use of cynomolgus monkey as the pharmacologically relevant species for toxicity assessments of telisotuzumab vedotin.”

“In vitro, telisotuzumab bound to cells overexpressing human or monkey c-Met with EC50 values of 1.3 and 1.5 nM, respectively, but did not bind to cells expressing mouse, rat, or rabbit c-Met.”

“DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2 protein but not to mouse or rat HER2 proteins, showing that the cynomolgus monkey is an appropriate species in which to conduct toxicity evaluation with DS-8201a, based on its binding to HER2.”

“In the same assay, DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2-His protein (Kd [ED50] = 7.46 ng/mL and 6.77 ng/mL, respectively) but not to mouse or rat HER2-His proteins.”

“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”

“it was previously demonstrated that trastuzumab binds to the Cynomolgus monkey receptor with similar affinity as to human HER2, but does not bind with high avidity to the rat receptor indicating Cynomolgus monkey is the more relevant pharmacologic species.”

“In view of the absence of cross-reactivity of gemtuzumab ozogamicin with CD33 from laboratory species, studies of kinetics in animals can only be of limited value, as there will be no binding, specific intracellular uptake, and metabolism of the conjugate that underlies its therapeutic action in humans.”

“hP67.6 bound strongly to human CD33-transfected CHO cells but did not bind to the monkey CD33-transfected CHO cells (study 084032).”

“Binding affinity of enfortumab vedotin to Nectin-4 was similar between humans, cynomolgus monkeys, and rats, but enfortumab vedotin bound to murine Nectin-4 at 10-fold lower affinity, thus supporting the use of the rat and monkey in the nonclinical toxicology studies.”

“Orthologs of Nectin-4 share >99%, ~94%, and ~92% homology to the human protein in cynomolgus monkeys, rats, and mice, respectively.”

“Polatuzumab does not bind to its target epitope on species typically used in toxicology studies. Both polatuzumab vedotin and a surrogate ADC that binds monkey CD79b were used in the toxicology studies.”

“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region.”

“The data suggests that the cynomolgus monkey was the only relevant toxicological species.”

“Tisotumab did not bind to mouse, rat, rabbit, pig, or dog TF.”

“Cynomolgus monkeys were identified as the only relevant toxicity species due to cross-reactivity of the target, Trop-2 with the hRS7antibody, the binding moiety of sacituzumab govitecan.”

“Despite approx. 80% sequence homology at the protein level between human and rodent Trop-2, hRS7 did not bind to mouse and rat Trop-2.”

“No pharmacologically relevant nonclinical species for safety evaluation—as defined in ICH S6(R1)—exists for loncastuximab tesirine, due its antibody component being selective for human CD19.”

“The monoclonal antibody (mAb) component of loncastuximab tesirine, RB4v1.2, is selective for human CD19 and not cross‐reactive with CD19 from any nonclinical species.”