The human CD47 (hCD47) not only protects tumor cells from phagocytosis by macrophages, but also dominates the clearance and balance of red blood cells in the body. Recent clinical trials showed that the utilization of single drug targeting hCD47 induced toxicity in human bodies. Thus, modification of anti-hCD47 antibodies and combinational usage with other therapeutics, such as anti-hPD-1 antibody might enhance the efficacy and lower the toxicity clinically. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hPD-1/hCD47 dual humanized mice for our clients all over the world.
Human programmed cell death protein 1 (hPD-1) is an immune checkpoint protein on the surface of T cells. The ligation of hPD-1 and human programmed cell death ligand 1 (hPD-L1) expressed on tumor cells emits a down-regulatory signal to T cells, and induces T cells to enter the static status. The anti-hPD-1 antibody has been approved by the FDA for malignant melanoma, non-small cell carcinoma, liver, stomach, kidney, bladder, head and neck cancers, Hodgkin lymphoma, Merkel cell carcinoma, and all solid tumor of highly unstable microsatellites (MSI-H).
hCD47 is a transmembrane glycoprotein with broad expression on multiple types of cells. Its other name is integrin-associated protein (IAP). It is often called as a “don’t eat me” signal because phagocytosis by macrophages is inhibited when hCD47 binds to the human signal regulatory protein alpha (hSIRPα) on macrophages. hCD47 dominates the clearance and balance of red blood cells in the body. However, the tumor cells escape immune surveillance via the hCD47/hSIRPα pathway. The drug targeting hCD47 theoretically could inhibit the immune evasion, and its efficacy has been investigated in various cancers including non-Hodgkin’s lymphoma, breast, ovarian, and small cell lung cancer.
The immune evasion of tumor cells occurs depending on the hPD-1/hPD-L1 signal pathway. The hCD47 expressed on the tumor cells could bind to hSIRPα on macrophages, inhibiting the phagocytosis of macrophages. Whether it is a monoclonal antibody targeting hCD47, or a fusion protein, the proven mechanism of action of these drugs mainly includes the four aspects: 1. promote apoptosis of tumor cells; 2. promote antigen presentation by dendritic cells (DCs); 3. inhibit phagocytosis by macrophages via blocking hCD47/hSIRPα; 4. evoke the antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effects by the Fc end of monoclonal antibodies. The last two are the core mechanism of actions of anti-hCD47 antibodies. Of these two effects, if the ADCC and CDC caused by Fc end are too strong, the anti-hCD47 antibodies would inevitably kill a large number of red blood cells, causing serious toxic reactions. If the effects mediated by the Fc end are completely discarded, and only relying on the biological functions of the hCD47/hSIRPα signaling pathway itself, it is not enough to activate a significant anti-tumor response. Thus, a new approach is proposed to combine anti-hCD47 antibodies with anti-hPD-1 antibody, and only taking advantage of the biological effects of hCD47/hSIRPα itself to release the anti-tumor potential of macrophages.
Fig.1 Mechanism of CD47-mediated antitumor activity. (Petrova, 2017)
Given the specificity of the hCD47 target, it is difficult for hCD47 single drug to achieve both effectiveness and safety, so the combination plan is promising. Since the anti-hPD-1 antibody has shown favorable efficacy in cancer patients, a combination of anti-hCD47 antibody with this immune checkpoint inhibitor might exhibit a synergistic effect in cancer treatment. With advanced technology, Creative Biolabs provides the hPD-1/hCD47 dual humanized mice for our global clients. If you are interested in this model, please feel free to contact us for more details. Our professional R&D team will provide you with scientific solutions to any of your study problems and assist you in your study project.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
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