The official website of the Center for Drug Evaluation (CDE) of the China State Food and Drug Administration announced that AK131 injection, a Class I new drug, has been approved for clinical use and is planned to be developed to treat advanced solid tumors, including but not limited to non-small cell lung cancer, esophageal cancer, pancreatic ductal adenocarcinoma, and liver cancer. Cell carcinoma etc. Public information shows that AK131 is a bispecific antibody targeting PD-1 and CD73.
CD73 is a key regulatory factor in tumor development and development, which can regulate tumor invasion and metastasis. The adenosine it catalyzes and hydrolyzes has immunosuppressive activity and plays an important role in tumor immune escape, which can lead to resistance to anti-PD-1 antibody therapy. CD73 and PD-1 are highly expressed in the tumor microenvironment, laying a mechanistic basis for anti-PD-1/CD73 antibody therapy.
According to public information, AK131 is a bispecific antibody targeting PD-1 and CD73, derived from AK105 (anti-PD-1 monoclonal antibody) and AK119 (anti-CD73 monoclonal antibody). AK131 can inhibit the ectonucleotidase activity of CD73 and reduce the accumulation of adenosine, thereby lifting the suppression of anti-tumor immune activity; it can also block the binding of PD-1 and its ligands PD-L1 and PD-L2 to relieve immune suppression. In addition, the antibody can also promote the activation of B lymphocytes through a pathway that is independent of CD73 enzyme activity, and has shown good anti-tumor activity in preclinical in vivo studies. By relieving tumor immunosuppression through complementary but non-overlapping pathways, AK131 is expected to become a new method for treating tumors.
In preclinical studies, AK131 has shown good in vivo and in vitro activity. In addition to effectively blocking the PD-1/PDL-1 interaction, it can also effectively promote the activation of T cells and B cells and induce the endocytosis of CD73. . In mouse models, AK131 showed good anti-tumor activity in vivo, inhibiting tumor growth by almost 100%.
Earlier at the 2022 American Association for Cancer Research (AACR) annual meeting, Kangfang Biotech released the preclinical research results of AK131.
• Research shows that AK131 can effectively block the interaction of PD-1/PD-L1 and has good anti-PD-1/PD-L1 activity.
• Inhibition of CD73 enzymatic activity was determined by cell-based enzymatic assay, AK131 showed potent inhibition of CD73 activity and stimulated cellular endocytosis of CD73.
• CD73 catalyzes the generation of adenosine from the substrate AMP, which has an immunosuppressive effect. When adenosine levels increase, the immune activating effect of anti-PD-1 antibodies is weakened. Cell experiments show that in the presence of adenosine generated by the hydrolysis substrate AMP of CD73, anti-PD-1 antibodies induce immune cell activation, and the activity of secreting IL-2 and other cytokines is significantly weakened, and because AK131 can simultaneously inhibit CD73 and PD-1 pathway, so it demonstrates stronger immune activation efficacy than anti-PD-1 monoclonal antibody alone, and the combination of PD-1 and CD73 monoclonal antibodies, and induces stronger IFN-γ and IL-2 of secretion.
• B cells are important players in the body's anti-tumor immunity, and studies have shown that B cell activation indicates a better prognosis. Cytological studies and previous in vivo pharmacological studies have suggested that AK131 can effectively induce B cell activation, and the expression of B cell activation marker molecules CD69, CD83, HLA-DR and IgM can be increased by AK131.
• The in vivo antitumor activity of AK131 was studied in C57BL/6-hPD-1/hPD-L1/hCD73 transgenic mice carrying MC38-hPDL1-hCD73 xenografts. Research shows that AK131 can significantly inhibit tumor volume growth and has relatively powerful anti-tumor activity.