In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model

Abstract

IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.

Isotype selection for antibody-based cancer therapy

“…Furthermore, tumour antigens released into the blood as monomers are not expected to induce crosslinking of FceR-bound IgE required for degranulation 44 . Consistently, no signs of anaphylaxis were found in preclinical models and safety data was satisfactory in both rodents and monkeys 44,47,48 .…”

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

“…We confirmed target antigen recognition by the antibody and its ability to be internalized by antigen-expressing tumor cells using a reporter assay. Previous studies have shown that CSPG4-expressing tumors could be targeted with CSPG4-specific agents [38][39][40][41]. This included the monoclonal antibody Ep1 to deliver cisplatin encapsulated in protein cages [42].…”

Isotype selection for antibody-based cancer therapy

“…Although tumour antigens released into the blood as monomers are not expected to induce cross‐linking of FcɛR‐bound IgE required for degranulation [54], circulating tumour cells expressing multiple copies of targeted antigen would have the potential to induce degranulation. However, no signs of anaphylaxis were found in preclinical models and safety data were satisfactory in both rodents and monkeys [54,57,58], supporting the initiation of the first clinical trial using a tumour‐targeting anti‐folate receptor alpha IgE mAb MOv18 (NCT02546921). Interim Phase I data from 24 patients support the safety and potential efficacy of MOv18 IgE [59].…”