As a continuation of a successful Phase I SBIR, this Phase II application is directed towards the further development of a novel immunocytokine, named 20-2b, for improved therapy of B-cell lymphomas. In the United States, there were 65,980 new cases of non-Hodgkin lymphoma (NHL) and 19,500 deaths from this disease in 2009. Of all B-cell NHL, 55% are of the DLBCL type, only half of which are curable. The remainder comprises indolent lymphomas (45%), none of which are curable. For 75% of all NHL patients newly diagnosed and a higher percentage of those alive at any time with evidence of disease, there remains a need for more effective treatments for these diseases, especially the incurable indolent types. Interferon-alpha-2 (IFNa2) is indicated for the therapy of a variety of hematopoietic and solid tumors. Combination therapy of NHL using IFNa2 and the anti-CD20 monoclonal antibody (MAb) rituximab is more effective than either agent as a monotherapy. However, the therapeutic potential of IFNa2 has not been fully realized primarily due to its short circulating half-life and systemic toxicity. Fusion of IFNa2 to a MAb markedly increases its circulating half-life, allowing less frequent administration of a single agent at a considerably lower dose than given for each agent in combination therapy. Targeting with an anti-CD20 MAb results in an increased and durable local concentration of IFNa2 at the sites of NHL while limiting its systemic concentration. This approach would significantly limit or eliminate many side effects and may result in an efficacy that is far superior to what is achievable using combination therapy. 20-2b was generated using the Dock-and-Lock (DNL) method to comprise 4 IFNa2b groups site-specifically tethered to the humanized anti-CD20 MAb, veltuzumab, for targeted delivery of IFNa2b to NHL. Successful product and process development, as well as extensive biochemical and biological characterizations of 20-2b were accomplished during Phase I. These very encouraging results reinforce Immunomedics commitment to the clinical investigation and ultimate commercialization of 20-2b. Initial clinical trials will be performed in relapsed/refractory indolent lymphoma, with additional expansion to other forms of NHL once these initial safety/efficacy studies are completed. To fulfill these clinical goals, this Phase II application will be concerned primarily with the finalization of the manufacturing process and the completion of regulatory requirements, which include qualification of master cell banks, validation of the cGMP manufacturing process and production of cGMP lots of 20-2b sufficient for performing safety testing in Cynomolgus monkeys and initial clinical trials. Upon completion, an IND for Phase I clinical trials will be submitted to FDA. Because the safety and efficacy of both IFNa2b and veltuzumab are well established from extensive clinical investigation, there is considerable potential for clinical and commercial success of 20-2b in NHL therapy.
The prototype construct investigated in this project, 20-2b, is a candidate therapeutic biologic agent for the treatment of B-cell malignancies including NHL and CLL, which may be refractory to the current front-line therapies. The lessons learned from this project may eventually lead to the development of additional MAb-IFNa for therapy of a variety of hematopoeitic and solid tumors.