ACP McElwain Prize – Antibodies of the IgE class: Preclinical evaluations for therapeutic use in the treatment of solid tumours


Year:

Session type:

Debra Josephs
King's College London and Guy's and St Thomas' Hospitals, London, UK

Background

All antibody cancer therapeutics rely on only one class, namely IgG. Although efficacious, IgG binds with low affinity to immune cell receptors and is subject to inhibitory mechanisms. Other antibody classes, namely IgE, may demonstrate superior tissue bioavailability and higher receptor affinity, which may in turn result in improved efficacy. MOv18 IgE against the ovarian carcinoma antigen, folate receptor alpha (FR) is a novel system to model this hypothesis.

A safety concern for IgE immunotherapy is induction of effector cell activation (anaphylaxis) in the circulation. To assess this, two model systems were adopted. One measured release of a granule-stored mediator from a basophilic cell line (RBLSX-38); the other measured CD63 expression, a marker of activation on blood basophils. MOv18 IgE alone, or with recombinant FR, healthy volunteer or ovarian carcinoma patient sera, did not induce RBLSX-38 degranulation. In addition, MOv18 IgE did not induce CD63 expression on basophils from healthy volunteers or cancer patients, despite detectable circulating FR. Exposure to FR-expressing tumour cells, however, at target-to-effector ratios expected within tumours, induced degranulation.

To examine the efficacy and safety of MOv18 IgE, an immunocompetent surrogate rat model of FR-expressing carcinoma was developed. Surrogate rat-MOv18 IgE and IgG2b antibodies were cloned, expressed and purified, and both demonstrated functionality. Systemic administration of MOv18 IgE and IgG2b at doses of 1-50mg/kg demonstrated significantly superior efficacy of MOv18 IgE compared to IgG2b. Furthermore, administration of MOv18 IgE for the first time in an animal expressing the full complement of IgE-receptor-expressing immune cells revealed no additional clinical nor histopathological toxicities compared to IgG2b. Finally, in vivo, ex vivo and in vitro assays revealed important roles for tumour-associated-macrophage activatory and migratory pathways, including upregulation of a unique cytokine signature. These findings are of pivotal significance to the translation of the first IgE class antibody towards first-in-human clinical trials.