Although toxicology studies should always be conducted in pharmacologically relevant species, the specificity of many biopharmaceuticals can present challenges in identification of a relevant species. In certain cases, that is, when the clinical product is active only in humans or chimpanzees, or if the clinical candidate is active in other species but immunogenicity limits the ability to conduct a thorough safety assessment, alternative approaches to evaluating the safety of a biopharmaceutical must be considered. Alternative approaches, including animal models of disease, genetically modified mice, or use of surrogate molecules, may improve the predictive value of preclinical safety assessments of species-specific biopharmaceuticals, although many caveats associated with these models must be considered. Because of the many caveats that are discussed in this article, alternative approaches should only be used to evaluate safety when the clinical candidate cannot be readily tested in at least one relevant species to identify potential hazards.

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 () as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models , including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation. We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. .

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.

Fc receptors are a critical component of the innate immune system responsible for the recognition of cross-linked antibodies and the subsequent clearance of pathogens. However, in autoimmune diseases, these receptors play a role in the deleterious action of self-directed antibodies and as such are candidate targets for treatment. GMA161 is an aglycosyl, humanized version of the murine antibody 3G8 that targets the human low-affinity Fcγ receptor III (CD16). As CD16 expression and sequence have high species specificity, preclinical assessments were conducted in mice transgenic for both isoforms of human CD16, CD16A, and CD16B. This transgenic mouse model was useful in transitioning into phase I clinical trials, as it generated positive efficacy data in a relevant disease model and an acceptable single-dose safety profile. However, when GMA161 or its murine parent 3G8 were dosed repeatedly in transgenic mice having both human CD16 isoforms, severe reactions were observed that were not associated with significant cytokine release, nor were they alleviated by antihistamine administration. Prophylactic dosing with an inhibitor of platelet-activating factor (PAF), however, completely eliminated all signs of hypersensitivity. These findings suggest that (1) GMA161 elicits a reaction that is target dependent, (2) immunogenicity and similar adverse reactions were observed with a murine version of the antibody, and (3) the reaction is driven by the atypical hypersensitivity pathway mediated by PAF.

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