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Removal of the core fucose from the Fc region of humanized monoclonal antibodies (afucosylated antibodies) enhances their antibody-dependent cell cytotoxicity activities in killing cancer cells. Based on the authors’ experience and literature, administrations of afucosylated antibodies have been associated with neutropenia in cynomolgus monkeys. However, in a recent general toxicology study conducted with an afucosylated antibody in cynomolgus monkeys, transient neutropenia was observed and correlated with the emergence of anti-drug antibodies (ADAs) in the affected animals. To further explore the relationship between neutropenia, afucosylated antibodies, and ADAs in cynomolgus monkeys, we performed an investigational retrospective meta-analysis of data from general toxicology studies conducted with Genentech’s therapeutic antibodies administered to cynomolgus monkeys between 2005 and 2021. In this analysis, transient neutropenia strongly correlated with ADA-induced inflammation in cynomolgus monkeys administered afucosylated antibodies. This may reflect the simultaneous occurrence of two distinct processes of neutrophil elimination and utilization, thus overwhelming bone marrow reserve capacity leading to transient neutropenia. The integrated analysis of immunogenicity, and anatomic and clinical pathology results from these studies highlights the correlation of transient neutropenia in cynomolgus monkeys with ADA-related inflammation, potentially exacerbated by enhanced effector function of afucosylated antibodies.

Integrating clinical pathology data with anatomic pathology data is a common practice when reporting findings in the context of nonclinical toxicity studies and aids in understanding and communicating the nonclinical safety profile of test articles in development. Appropriate pathology data integration requires knowledge of analyte and tissue biology, species differences, methods of specimen acquisition and analysis, study procedures, and an understanding of the potential causes and effects of a variety of pathophysiologic processes. Neglecting these factors can lead to inappropriate data integration or a missed opportunity to enhance understanding and communication of observed changes. In such cases, nonclinical safety information relevant to human safety risk assessment may be misrepresented or misunderstood. This “Points to Consider” manuscript presents general concepts regarding pathology data integration in nonclinical studies, considerations for avoiding potential oversights and errors in data integration, and focused discussion on topics relevant to data integration for several key organ systems including liver, kidney, and cardiovascular system.