Anti-Tumor Activities of Anti-Siglec-15 Chimeric Heavy-Chain Antibodies

TL;DR

This paper explores new antibodies targeting Siglec-15, a protein involved in cancer, showing promising anti-tumor effects in mice.

Contribution

The study introduces chimeric heavy-chain antibodies against Siglec-15 with demonstrated anti-tumor activity in a mouse model.

Findings

Three anti-Siglec-15 antibodies (S1, S5, S6) showed specific binding to human and murine Siglec-15.

S1 treatment significantly reduced tumor size and increased tumor-associated macrophages in mice.

The antibodies blocked Siglec-15 interactions with multiple ligands and reduced pro-inflammatory cytokines.

Abstract

Immune checkpoint inhibitors like programmed cell death 1 (PD-1) antibodies have revolutionized cancer treatment, but patient response rates remain limited. Sialic acid-binding Ig-like lectin 15 (Siglec-15) has emerged as a promising new immune checkpoint target. Through phage display technology using a Bactrian camel immunized with recombinant human Siglec-15, we generated six anti-Siglec-15 camelid nanobodies and constructed chimeric heavy-chain antibodies by fusing the VHH domains with human IgG-Fc. Following expression in HEK293-F cells and purification, three antibodies (S1, S5, S6) demonstrated specific binding to both human and murine Siglec-15 in ELISA and biolayer interferometry assays. In a xenograft model established by subcutaneous inoculation of NCI-H157-S15 cells into BALB/c nude mice, these antibodies showed distinct tumor targeting and significant blockade of Siglec-15 interactions with CD44, MAG, sialyl-Tn, and LRR4C ligands. All three antibodies exhibited anti-tumor effects, with S1 showing the most potent activity. S1-treated mice had significantly smaller tumor volumes and weights compared to controls. The S1, S5, and S6 treatment groups showed enhanced anti-tumor immunity, with reduced TGF-β, IL-6, and IL-10 levels. Notably, S1 treatment significantly increased tumor-associated macrophages in tumor tissues (p < 0.05). In conclusion, S1 exhibits remarkable anti-tumor activity and has the potential to be developed as a cancer immunotherapy targeting Siglec-15.

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