HONG KONG, Dec. 12, 2022 /PRNewswire/ — Akeso Inc. (9926. HK) (“Akeso”) today announced that the Journal for Immunotherapy of Cancer (JITC), a BMJ oncology journal, published the mechanism of action of its Ligufalimab (AK117). The article’s name is “Ligufalimab, a novel anti-CD47 antibody with no hemagglutination that demonstrates both monotherapy and combo antitumor activity”. The results showed the promising antitumor efficacy and favorable safety profile of AK117. The unique mechanism of action AK117 was also published at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meetin g (SITC 2021).
AK117 is a novel humanized IgG4 anti-CD47 antibody without hemagglutination effect developed by Akeso Independently. AK117 promotes phagocytosis of tumor cells and improves the antitumor efficacy without requiring a lower ‘priming’ dose to prevent anemia. This article comprehensively elaborates on the safety breakthrough and antitumor activity of AK117 as a new generation of CD47 monoclonal antibody alone or in combination from a mechanistic point of view. AK117 is expected to lead to better efficacy and safety in clinical practice and the expansion of indications.
The JITC publication includes the following findings:
AK117 specifically binding human CD47 with high affinity and blocking of SIRPα interaction with CD47
AK117 can specifically bind human CD47 with high affinity. And AK117 effectively blocked the CD47-SIRPα interaction on the surface of tumor cells, and the blocking activity of AK117 was comparable to that of Hu5F9-G4.
AK117 does not induce RBC agglutination related to the binding epitopes
CD47 is ubiquitously expressed on various human cells, including RBCs and platelets. The main treatment-related adverse events of CD47 blocking antibodies are hematotoxicities, especially hemagglutination and anemia. The hemagglutination test showed that AK117 did not induce RBC hemagglutination even at concentrations up to 3000 nM, while Hu5F9-G4 induced RBC hemagglutination at concentrations as low as 4.1 nM.
The different binding orientations of AK117 and Hu5F9-G4 on CD47 might be related to the distinct binding epitopes of AK117 and Hu5F9-G4. The AK117/CD47 complex formed a smaller angle, hinting that AK117 is unlikely to bind two cells simultaneously. However, the big distance between two bound CD47 proteins is more allowable for Hu5F9-G4 to bind CD47 on two different cells, resulting in RBC agglutination.
AK117 promotes phagocytosis of tumor cells and demonstrates antitumor activity in a mouse model
AK117 induces phagocytosis of tumor cells in a dose-dependent manner and improves the antitumor efficacy, with activity similar to that of Hu5F9-G4. AK117 demonstrates robust antitumor activity in a mouse model, and antitumor activity of AK117 was significantly higher than that of Hu5F9-G4 at the dose of 0.02 mg/kg.
AK117 demonstrates robust antitumor activity of AK117, as monotherapy or in combination with AK112
The results demonstrated that tumor growth was effectively inhibited in monotherapy and combination therapy groups, and a dramatic inhibition effect was observed in the AK117 and AK112 combination group with statistically significant differences, and no obvious body loss of mice was found in all groups.
AK117 shows a favorable safety profile in non-human primates compared with Hu5F9-G4.
The toxicologic assessment of AK117 was performed in cynomolgus monkeys. AK117 did not induce RBC hemagglutination in cynomolgus monkeys. Compared with Hu5F9-G4, AK117 caused less anemia and quickly recovered with better safety.
Based on preclinical data and early clinical results, a series of phase IB/II clinical studies of AK117 combined with various agents for the treatment of a number of cancer types are in progress (NCT04900350, NCT04980885, NCT05227664, NCT05229497, NCT05214482, NCT05235542, NCT05382442).