A NOVEL PLATFORM FOR MULTI-SCALE CAMOUFLAGING OF THERAPEUTIC PROTEINS
Abstract
Therapeutic mAbs offer a significant opportunity as prophylactic and therapeutic medical countermeasures (MCMs) against biological and chemical warfare agents. Many of the mAbs developed against these hreats have non-human origins (e.g., mouse, rat), which are associated with undesirable properties including the elicitation of immunogenic responses and short persistence in serum. Protein engineering strategies for sequence humanization and enhancing neonatal Fc receptor (FcRn) binding are commonly used to reduce immunogenicity and improve PK behavior, respectively. However, the sequence changes required to achieve these objectives are often deleterious to antigen binding and/or Fc effector functions. Moreover, many human/humanized mAbs still trigger unwanted host immune responses leading to immunogenicity. To address these issues, the proposed work seeks to create a multidimensional camouflaging technology for spawning mAb variants with reduced immunogenicity and enhanced PK properties. Specifically, custom epitope deletion and glycan masking methods will be integrated to mitigate sequences within mAbs that trigger immune recognition, promote selfaggregation, and contribute to electrostatic interaction with the negatively charged surfaces of epithelial cells. The research uniquely combines: (i) broadly applicable computational and experimental protein design algorithms that balance mitigation of undesirable traits with tability and function; (ii) a cutting-edge cell-free expression system for producing therapeutic proteins with customized glycosylation; and (iii) high-throughput screening technologies for experimentally uncovering he structural, functional, and immunological consequences of camouflaging. Overall, the generality and integration of this platform will provide an entirely new approach for simultaneously controlling mmunogenicity, stability, half-life, and efficacy of virtually any therapeutic protein.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 04, 2021
- Source ID
- HDTRA12010004
Entities
People
- Matthew P. DeLisa
Organizations
- Cornell University
- Defense Threat Reduction Agency