141P - An IgE antibody targeting the melanoma-associated Chondroitin Sulfate Proteoglycan 4

Background

In antibody-mediated oncotherapy, IgG monoclonal antibodies have been the class of choice for the treatment of different cancers. However, tumour-antigen specific IgE antibodies are emerging as a new avenue for cancer therapy. This class of antibody have a high affinity for cognate Fcε receptors expressed on tumour-resident immune cells, such as macrophages and mast cells, and a lack of inhibitory Fc receptors, offering the chance to activate anti-tumour responses in tissues. Recently, a tolerable safety profile and anti-tumour efficacy of an IgE antibody recognizing the tumour-associated antigen, folate receptor α (FRα), has been shown in the first-in-class clinical trial of this agent.

Methods

We engineered a monoclonal IgE antibody, with human constant domains, recognising CSPG4 to target human melanoma. In vitro Fab-mediated antitumour effects, and mediated antibody-dependent cellular cytotoxicity (ADCC) against melanoma cells by immune effector cells were evaluated. CSPG4 antigen may be cleaved and released from the surface of tumour cells, and may bind to anti-CSPG4 antibodies, preventing them from engaging tumour cells and impairing their anti-tumour efficacy; or complexes of shed CSPG4 may cross-link anti-CSPG4 IgE engaged with basophils, which could potentiate degranulation and type I hypersensitivity. CSPG4 antigen shedding was measured in melanoma cell supernatant and in human sera. As an early evaluation of safety, we tested the propensity for CSPG4 IgE to induce RBL-SX38 degranulation in the presence of melanoma patient sera, and in unfractionated patient blood in basophil activation tests (BAT).

Results

CSPG4 IgE bound to melanoma tumours, induced Fab-mediated antitumour effects, and mediated ADCC against melanoma cells. We measured minimal shedding of the CSPG4 antigen in melanoma cell supernatants. Low levels of CSPG4 were detected in the circulation of melanoma patients and healthy subjects, with no significant difference in levels between the groups. CSPG4 IgE did not trigger RBL-SX38 degranulation and did not activate basophils in the BAT assay, suggesting lack of propensity to trigger anaphylaxis.

Conclusions

Our findings suggest that CSPG4 IgE may be an efficacious and safe immunotherapy for melanoma.

Legal entity responsible for the study

The authors.

Funding

Epsilogen Ltd.

Disclosure

All authors have declared no conflicts of interest.