Harnessing Antibody Polyspecificity for Cancer Immunotherapy.

Area of Science:

• Immunology
• Glycobiology
• Cancer Research

Background:

• Tumor cell heterogeneity necessitates targeting diverse tumor-associated carbohydrate antigens (TACAs).
• Naturally occurring, polyspecific antibodies offer potential in cancer immunotherapy by recognizing pathogen-like glycan structures on tumors.
• Existing antibodies can be harnessed to develop novel cancer therapeutics.

Purpose of the Study:

• To rationally design carbohydrate mimetic peptides (CMPs) that mimic tumor-associated carbohydrate antigens (TACAs).
• To develop CMPs with cross-reactivity to GD2 and Lewis Y (LeY) reactive antibodies for cancer therapy.
• To utilize CMPs as templates for inducing biosimilar polyreactive antibodies.

Main Methods:

• Rational design of CMPs based on structural analyses and molecular modeling.
• Utilizing CMPs to affinity-purify human antibodies and analyze glycan reactivity patterns.
• Investigating antibody binding to the lacto-ceramide core (Galβ(1,4)Glcβ(1-1')Cer) for therapeutic applications.

Main Results:

• Developed CMPs demonstrating reactivity to GD2 and LeY antibodies.
• Characterized molecular features of CMP mimicry, including polyspecificity of LeY and GD2 reactive antibodies.
• Identified the lacto-ceramide core as a key binding target for cancer therapy and diagnostics.

Conclusions:

• CMPs can effectively mimic TACAs, leveraging natural antibody polyspecificity for cancer treatment.
• The lacto-ceramide core represents a promising target for developing novel cancer vaccines and diagnostics.
• This approach offers a new strategy for cancer vaccine design by exploiting natural antibody repertoires.