In Situ Tumor Surface Modification with Antibody Fragments for Antigen-Independent Versatile Cancer Immunotherapy

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Natural killer (NK) cells are crucial for tumor immunity via antibody-dependent cell-mediated cytotoxicity (ADCC).
• Tumor antigen heterogeneity limits the effectiveness of traditional ADCC-based therapies.
• A method for antigen-independent NK cell activation is needed to broaden cancer treatment options.

Purpose of the Study:

• To develop a novel platform for antigen-independent cancer cell targeting by NK cells.
• To engineer a Universal Antibody (Univody) for broad applicability across diverse cancer types.
• To evaluate the efficacy of the Univody system in preclinical cancer models.

Main Methods:

• Construction of a recombinant fusion protein (Univody) linking Fc fragments to a transmembrane domain.
• Delivery of Univody-encoding plasmid DNA using phenylboronic acid-modified lipopolyplexes (LPP-PBA).
• Assessment of Fc fragment presentation on cancer cells and NK cell activation.
• Preclinical in vivo studies in triple-negative breast cancer and melanoma models.

Main Results:

• Univody successfully decorated heterogeneous cancer cells with Fc fragments in an antigen-independent manner.
• LPP-PBA facilitated efficient cellular uptake and transfection, enhancing Univody delivery.
• Univody treatment activated NK cells and promoted anti-tumor immune responses.
• Significant tumor inhibition was observed in treated triple-negative breast cancer and melanoma models.

Conclusions:

• The Univody platform offers a versatile strategy for enhancing NK cell-mediated immunotherapy.
• This antigen-independent approach overcomes limitations of traditional antibody therapies targeting specific tumor antigens.
• Univody holds promise for a broader range of cancer treatments, including immunotherapy and antibody therapy.