Summary
A chimeric IgE class anti-CSPG4 antibody has been developed which has demonstrated positive results in vitro and in vivo. The antibody is designed to target immune responses directly against melanoma tumour cells, circumventing the broad immune activatory properties of currently approved immunotherapies.
Figure: CSPG4 IgE restricts growth of an A375 human melanoma xenograft grown subcutaneously compared to CSPG4 IgG1 (**p<0.01) and non-specific antibody isotype controls when administered intravenously in a humanised mouse model with splenic engraftment of human immune effector cells.
Background
Malignant melanoma remains largely refractory to treatments. Single agent chemotherapies such as dacarbazine, currently standard of care in the UK, have very limited efficacy. Few patients (5-15%) benefit from adjuvant therapies (high-dose IL-2, IFN-α2b) which are associated with highly toxic side effects, making their wider clinical use largely impractical. Adoptive cell therapies, using patient-derived immune cells to enhance patient immunity, have shown some promise but are difficult to apply widely. Two drugs for the treatment of late stage melanoma were recently approved by the FDA: Ipilimumab (Yervoy, Bristol-Myers Squibb, INC) and Vemurafenib (Zelboraf or PLX4032) developed by Plexxikon/Hoffmann–La Roche. These drugs are effective in only subsets of the patient population and are associated with serious side-effects and patient relapse.
Development
Using an in-house expression cloning platform, we have engineered two chimeric monoclonal antibodies of the same specificity against cell surface chondroitin sulfate proteoglycan CSPG4, from the variable region sequences of a mouse antibody, one with Fc regions belonging to the IgG1 subclass and the other with IgE Fc regions. Our in vitro functional studies to-date confirm that each antibody can induce tumour cell death by a number of mechanisms. Treatment with anti-CSPG4 IgE restricts tumour growth more effectively compared to the IgG1 counterpart in our subcutaneous human xenograft model of melanoma. Further evaluations of antibody efficacy are on-going, and optimal dosing and early readouts of safety will be conducted using a combination of in vitro assays and in vivo human xenograft models of melanoma in mice engrafted with human immune effector cells.
Features & Advantages
Antibodies with Fc regions of the IgE class:
- Numerous attributes of IgEs, such as natural immune activatory functions in tissues and high affinity for cognate receptors on frequently tumour-resident effector cells can translate into superior protection against solid tumours such as melanoma, compared to IgGs.
Choice of target, the cell surface chondroitin sulfate proteoglycan CSPG4:
- Over-expression by >80% of melanomas (not melanocytes), potentially benefiting many patients
- Restricted distribution, low expression in normal tissues would limit on-target toxicities
- Presence in tumour-associated pericytes may offer opportunities to restrict tumour blood supply
- Expression in primary and metastatic lesions, limited heterogeneity across tumours, translating to applications in adjuvant and advanced disease settings
Engineering of antibodies to CSPG4 and established model systems:
- Serum-free production and established purification processes are adoptable in GMP environments.
- Numerous in vitro and ex vivo assays of antibody function, potency and early assessments of safety in patient specimens
- Two in vivo human xenograft models of melanoma with splenic engraftment of human immune cells: a subcutaneous and a model of lung/liver metastases.
Promising efficacy for anti-CSPG4 IgE:
- Anti-CSPG4 IgE restricts tumour growth at less frequent doses compared to IgG1 in our subcutaneous model of melanoma.
Patent Status
A PCT patent application was filed on 4th October 2011 which claims the IgE antibody.