Durability of response is the hallmark of immunotherapy, but only a fraction of patients experience this prolonged benefit. Modification of cytokines by covalent attachment of a polymer such as polyethylene glycol (PEG) has classically been used to extend exposure and reduce renal clearance rate, thereby increasing the potential for a durable response. The next generation of polymer conjugation technology developed by Nektar enables more complex and profound modification of cytokine activity.
NKTR-214, an engineered form of IL-2 that directly activates cytotoxic T cells by targeting the IL-2 receptor beta subunit, has a pharmacokinetic profile more like an antibody than a cytokine. The polymer conjugation strategy was designed to improve efficacy and limit toxicities by optimizing biodistribution to the tumor, enhancing the PK profile through reduced Cmax and increased exposure, and by altering the receptor binding profile to enhance tumor killing. Without any changes to the amino acid sequence, this multi-PEGylated form of IL-2 demonstrates greatly improved efficacy in preclinical tumor models relative to IL-2. NKTR-214 directly stimulates cytotoxic T cells and therefore has a mechanism of action complementary to that of antibody-mediated checkpoint inhibition. Testing that complementary activity in preclinical models of cancer, synergism was achieved by combining NKTR-214 mediated T cell activation with CTLA-4 or PD1 blockade, holding the promise for extended, durable responses in patients who may benefit from agents with complementary immunological mechanisms. Data and discussion will address how this approach may be generalized to enhance other cytokine-based therapies.
Seema Kantak has been Vice President of Preclinical Development at Nektar Therapeutics since 2010 and from 2010-2012 was also the Managing Director of Nektar's India subsidiary. She has 15 years of biopharmaceutical industry experience in discovery and R&D in biologics and small molecules for oncology, inflammation, cardiovascular and metabolic disorders as well as executive and operational management experience supporting multi-million dollar projects.
Prior to joining Nektar Therapeutics, Seema held positions of increasing responsibilities at XOMA (US) LLC, Celera Genomics and Axys Pharmaceuticals and participated in IND submissions and clinical development of both small molecule and antibody therapeutics.
She completed her post doctoral fellowship at the UCSF Cancer Center. She received her M.S and Ph.D. in cancer biology from Wayne State University, Michigan, an MS in biophysics from Bombay University, India and B.S. in microbiology from Bombay University, India. Seema Kantak has authored several scientific articles and written book chapters.