A-319 is a CD19/CD3 bi-specific antibody. It belongs to category 1 therapeutic biologicals according to NMPA guidelines. A-319 is produced in CHO cell in a serum-free medium and the manufacturing process is like that of a conventional antibody manufacturing. The A-319 drug product is a liquid formulation, which is stable over 6 years when stored at 4℃.
A-319 is developed to treat patients with B cell malignancies including pre-B cell acute lymphoblastic leukemia (B-ALL), B cell chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma (NHL) including its various sub-types.
Two Phase I clinical trials of A-319 almost completed to treat “relapse and refractory B-ALL” and “relapse and refractory NHL.”
An NDA filing to NMPA is expected in 2026.
B Cell Lymphoma
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes and develop more frequently in older adults and immunocompromised individuals. B-cell lymphomas include both Hodgkin's lymphomas (10%) and most non-Hodgkin lymphomas (90%). They are typically divided into low (indolent, 40%) and high (aggressive, 60%) grades.
According to the data reported in 2020, more than 544,000 patients are newly diagnosed, ranking 13 among all types of aggressive cancers. There are more than 4,000,000 NHL patients worldwide, with more than 200,000 deaths. In China, there were > 92,000 newly diagnosed NHL patients, with more than 54,000 deaths in 2020 (ref x).
More than 60 specific NHL subtypes have been identified and assigned names by the World Health Organization (WHO). The most common NHL subtypes include Diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), Marginal zone B-cell lymphoma (MZL) or mucosa-associated lymphatic tissue lymphoma (MALT), Small lymphocytic lymphoma (SLL, also known as chronic lymphocytic leukemia, CLL), and Mantle cell lymphoma (MCL).
Aggressive lymphomas usually require intensive treatments including chemotherapy,radiation,immunotherapy,targeted therapy,stem-cell transplantation and surgery, or a combination. The clinical outcome for treating an aggressive lymphoma with the current therapies remains a big challenge. In the case for DLBCL, after first line, or second line therapy, approximately 30% to 50% patients are resistant to drug therapy or relapse after remission. The 5-year survival is at about 50% .
Recently, CD19-CART and BCMA-CART have demonstrated significant benefits to patients and received regulatory approval. Except for the complexity of the manufacturing process and affordability to patients, the long-term survival data with a larger patient population remains to be demonstrated.
Acute Lymphoblastic Leukemia (ALL)
ALL is a type of aggressive B cell blood cancer. It is characterized by the development of large numbers of immature B lymphocytes in the bone marrow and lymph nodes with a wide range of clinical heterogenicity. ALL accounts for 10% of all leukemia cases and 30% to 40% of acute leukemia cases. Approximately 10,000 new cases are diagnosed annually in China. Globally, there are > 800,000 ALL patients, with 60,000 – 70,000 newly diagnosed cases and > 100,000 deaths annually. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.
ALL is typically treated initially with chemotherapy drugs aimed at bringing the disease to remission. Further chemotherapy is required for patients in remission over a few years.
After chemotherapy, 80% to 90% of adult ALL patients have diseases under control or in remission, while 50% of these patients will relapse over time. The relapse patients have little treatment options, and the median overall survival is about 3 months, while the 3-year survival is less than 10%.
Recently, CD19-CAR-T and blinatumomab (CD19/CD3) have demonstrated significant benefits to patients and received regulatory approval. In the case of CD19 CAR-T cell therapy, the major hurdles are the complexity of the manufacturing process, patient waiting period, and affordability. In the case of Blincyto, the safety and patient convenience are the two largest concerns. Recently, data has shown that 50% to 60% ALL patients relapse after receiving these therapies.
