CD47-SIRPα “Do-not-eat- me” signaling axis is myeloid-specific innate immune checkpoint. Cancer cells express CD47 on the cell surface enable them to evade detection by the innate immune system and thus avoid destruction by macrophages. Inhibition of CD47-SIRPα axis triggers phagocytosis by macrophages. Current therapeutic CD47 inhibitions include anti-CD47 monoclonal antibodies, bispecific antibodies and recombinant fusion protein. Anti-CD47 monoclonal antibodies are the most extensively studies for cancer immunotherapy. One potential risk in the development of anti-CD47 treatment is the so-called “antigen sink”. The ubiquitous expression of CD47 on healthy cells could act as “antigen sink” to soak up antibodies, and thus higher dose for a drug would be required to achieve an effective therapeutic blockade of CD47. In addition, these high doses of antibodies when administered intravenously would suppress the “don’t eat me” signal on red blood cells, prompting macrophages to engulf them.
Glutaminyl-peptide cyclotransferase-like protein (QPCTL, or isoQC) is a Golgi-resident enzyme that catalyzes the cyclization of N-terminal glutamine and glutamic acid residues on target protein into a pyroglutamate residue (pGlu). Our collaborator Dr. Andrew Wang and his research team at Academia Sinica have previously resolved the crystal structures of human glutaminyl cyclase (QC) and its isoform glutaminyl-peptide cyclotransferase-like protein (isoQC) and their functions. Recently, Logtenberg and colleagues reported that QPCTL is a key regulator of CD47. These investigators found that the formation of pyroglutamate on CD47 was essential for the binding of SIRPα on the macrophage as QPCTL KO or pharmacological inhibition selectively affects binding of SIRP𝛼 and anti-hCD47 antibody recognizing SIRP𝛼 binding site. In addition, gene expression data confirmed that isoQC is highly expressed in a variety of tumors, and the corresponding patient overall survival is significantly shortened. These data suggest that isoQC can be used as a potential drug target in cancer immunotherapy. Phagocytic activity can be further stimulated by cancer targeting antibodies via antibody-dependent cellular phagocytosis (ADCP) (Figure 1).
In collaboration with Dr. Andrew Wang at Academia Sinica, we have identified a potent and orally isoQC inhibitor DBPR22998 with isoQC inhibitory activity at sub-nanomolar range. DBPR22998 significantly reduced the binding of anti-CD47 antibody on cell surface and prevented the interaction of human SIRPα-Fc with cell surface CD47 in both solid tumors and hematologic cancer cell lines tested. In addition, DBPR22998 in combination with anti-CD20 antibody rituximab enhanced ADCP in a human B-cell lymphoma Raji cells. In vivo, oral administration of BPRQC298 in combination with anti-cancer monoclonal antibody was efficacious against multiple tumor types. In a B-cell lymphoma xenograft tumor model, combination therapy induced tumor regression and prolonged animal median survival time compared to anti-CD20 antibody rituximab alone. BPRQC298 compound exhibited excellent pharmacokinetic properties and good oral absorption. Based on the above findings, DBPR22998 was nominated as development candidate.
There are several potential advantages of targeting isoQC over therapies targeting CD47. First, isoQC inhibitors are not expected to cause hemolysis (lysis of red blood cells) and thrombocytopenia (loss of platelets). This is because red blood cells and platelets lack protein synthesis, and pyroglutamylated CD47 cannot be replaced by non-pyroglutamylated CD47 in these cells. Second, because isoQC is an enzyme, isoQC inhibitors would not suffer from the “antigen sink” problems of anti-CD47 therapy. Third, small molecule inhibitors of isoQC would have advantages over anti-CD47 antibodies in terms of bioavailability and delivery, which may be particularly beneficial for treating solid tumors. As opposed to antibody approaches in clinical development, our small molecule isoQC (QPCTL) inhibitor DBPR22998 represents an innovative therapeutic approach for boosting the efficiency of cancer immunotherapy by targeting post-translational modification process of CD47 protein synthesis instead of blocking CD47 on the cell surface.
The current invention is the first small molecule isoQC inhibitor developed in Taiwan. Patents of United States, the Republic of China, Japan, Korea, China and Australia are granted; patents in other countries are under review. IsoQC inhibitors are best used in cancer types that are prone to treatment resistance and recurrence. Our future plan is to license out or to collaborate with industrial partner to co-develop DBPR22998. It is expect that novel isoQC inhibitors will drive the growth of biotechnology and pharmaceutical industries to increase the demand of such cancer drugs.