In the past decade, monoclonal antibody therapy has achieved significant clinical outcomes in the field of cancer treatment. The research on mAbs targeting immune checkpoints brought benefits to thousands of patients. By the assistance of our advanced platforms and extensive experience in antibody discovery and development, Creative Biolabs is now proposing a variety of Next-IO™ programs to develop novel antibody therapeutics with our partners. This program aims to develop therapeutic monoclonal antibody (mAb) targeting Siglec-10, a ligand for novel CD24 deployed by cancer cells.
Siglec-10
Sialic-acid-binding Ig-like lectin 10 (Siglec-10) is expressed on the surface of immune cells. Its’ cytoplasmic domain contains two Immunoreceptor tyrosine-based inhibitory motif (ITIM). Siglec-10 was identified to be ligands for CD52 and Vascular adhesion protein 1 (VAP-1), and most recently, for CD24. The CD24-Siglec-10 interaction is known to induce an inhibitory cascade and suppress the anti-tumor immunity via blocking toll-like receptor-mediated immunity and the cytoskeletal rearrangements.
Fig.1 Schematic-depicting interactions between macrophage expressed Siglec-10 and CD24 expressed by cancer cells.1
Our Anti-Siglec-10 Monoclonal Antibody Program
Studies have shown Siglec-10 is over-expressed in tumor-associated macrophages (TAMs) and blocking Siglec-10 can increase phagocytosis. The Siglec-10 receptor, CD24, is demonstrated as an important “don’t eat me” signal and blocking of such interaction with genetic ablation or mAb can restore the anti-tumor immunity mediated by TAMs. Here are some features of CD24-Siglec-10.
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CD24 can promote immune evasion through interaction with Siglec-10;
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Siglec-10 is highly expressed on tumor-associated macrophages;
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Blocking CD24-Siglec-10 interaction through genetic ablation or monoclonal antibodies can enhance the phagocytosis of CD24-expression in human tumor cells;
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Blocking CD24-Siglec-10 interaction may slow down tumor growth and increased survival rate in vivo.
From the data, it reveals CD24 has therapeutic potential in cancer immunotherapy. Our program aims to discover and develop novel therapeutic monoclonal antibodies against CD24. Except for mAb therapy, we also interests in combination therapies or other antibody modalities. We are dedicated to developing valuable pipelines with our partners!
Fig.2 Blocking CD24-Siglec-10 interaction promotes phagocytic clearance of cancer cells.1
Published Data
Our program is developed using a basic principle that blocking Siglec-10 can boost macrophage-dependent phagocytic clearance of CD24-expressed tumor cells. Here are some published data on CD24-Siglec-10:
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CD24 is over-expressed in ovarian cancer cells and breast cancer cells; Siglec-10 over-expression in tumor-associated macrophages are also elevated.
Fig.3 Left, representative histogram of CD24/Siglec-10 expression by ovarian cancer cells/TAMs or breast cancer cells/TAMs. Right, frequency of CD24+ cancer cells/Siglec-10+ TAMs in ovarian cancer or breast cancer.1
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Anti-Siglec-10 mAb enhances the phagocytosis of TAMs in wild-type MCF-7 cells.
Fig.4 Phagocytosis of wild-type MCF-7 cells, in the presence of anti-Siglec-10 mAb or IgG.1
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Treatment with anti-CD24 mAb promotes phagocytic clearance of human cancer cells.
Fig.5 Phagocytosis of MCF-7, APL1, Panc1 and U-87 GM cell line and primary ovarian cancer cells in the presence of anti-CD24 mAb, anti-CD47 mAb or dual treatment, compared with IgG control.1
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Siglec-10 knock out macrophages promote phagocytic clearance of wild-type MCF-7 cells.
Fig.6 FACS-based measurement of Siglec-10 expression, frequency of Siglec-10+ macrophage and phagocytosis of wild-type MCF-7 cells in indicated groups.1
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Treatments with anti-CD24 mAb or genetic ablation inhibit the tumor growth and improve the survival curve.
Fig.7 Representative bioluminescence images of tumours in mice and survival analysis of mice with different treatment groups.1
We have extensive experience in performing comprehensive program developments and effective problem-solving. For our Next-IO™ programs, we are committed to promoting the program to pre-IND stage within about 1.5 years. Accurate timeline will be determined on a case-by-case basis. Here is a draft timeline for your glance.
Fig.8 Project pipeline management of therapeutic monoclonal antibody.
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