Long Acting PEG-Like Conjugates of an Immune Checkpoint Inhibitor and a Selective Cytokine for Combination Immunotherapy
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment by restoring the ability of T cells to recognize and destroy tumor cells, resulting in an unprecedented anti-cancer immune response and efficacy. However, despite their remarkable success in treating many malignancies, not all tumors fully respond to ICI monotherapy due to their poorly immunogenic nature, low T cell infiltration into the tumor bed, and insufficient T cell activation. Efficacy may also be limited by the low tumor penetration of monoclonal antibodies (mAbs) the tumor-targeting ICIs of choice due to their large size and structural inflexibility. To further activate T cells, combination therapies with cytokines, such as interleukin-15 (IL-15) and IL-2 (aldesleukin), have been utilized. Unfortunately, these treatments result in life-threatening systemic toxicity and ambiguous clinical efficacy due to their non-selective nature. Furthermore, even if these problems are solved, the short plasma half-life (approx. 1.4 h) of IL-2 and IL-15 limits their therapeutic utility. PEGylation the conjugation of PEG to biologics is commonly used to overcome this limitation. Unfortunately, PEG is antigenic, which has caused severe allergic reactions in some patients and has led to the withdrawal of several PEGylated drugs from the market and termination of Phase III clinical trial of a PEGylated drug candidate. These problems have been traced to pre-existing PEG antibodies found in approx. 50% of the U.S. population and even in individuals who have not previously received a PEGylated drug. Hence, there is an unmet need for immunotherapy that provides high anti-cancer efficacy and overcomes the low tumor penetration of mAbs and the toxicity, lack of selectivity, and pharmacokinetic (PK) limitations of cytokines using technologies beyond PEGylation. Here, we developed hyperbranched PEG-like polymer conjugates of a selective anti-cancer cytokine.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1152465
Entities
People
- Imran Ozer
Organizations
- Duke University