Harnessing Antibody Polyspecificity for Cancer Immunotherapy

Targeting the diverse glycan repertoire expressed on tumor cells is considered a viable therapeutic strategy to deal with tumor cell heterogeneity. Inherently polyspecific, natural, glycan-reactive antibodies are purported to be protective in thwarting infections and in cancer immunotherapy. Tumor-associated carbohydrate antigens (TACAs) are related to pathogen glycans, to which nascent or natural antibodies exist and IgM responses are elicited. To capture the polyspecific nature of anticarbohydrate responses, we have focused on the rational design of carbohydrate mimetic peptides (CMPs) cross-reactive with TACA reactive antibodies. In particular, we have focused on the development of CMPs that display reactivity to GD2 and Lewis Y (LeY) reactive monoclonal antibodies. They would serve as templates for pan-immunogens inducing biosimilar polyreactive antibodies. In the design, we relied on structural analyses of CMP's enhanced binding to the templates using molecular modeling. Glycan reactivity patterns of affinity CMP-purified human antibodies further refined specificity profiles in comparison with the immune response to the CMP in clinical trials. In this study, we further define the molecular characteristics for this mimicry by considering the polyspecificity of LeY and GD2 reactive antibodies binding to the lacto-ceramide core Galβ(1,4)Glcβ(1-1')Cer. Binding to this minimum building block can be capitalized on for cancer therapy and diagnostics and illustrates a new approach in designing cancer vaccines taking advantage of the latent polyspecificity of antibodies and the relevance of natural antibodies in antigen discovery and design.