Accelerating Next-Generation Vaccine Development for Global Disease Prevention
Koff, W. C. et all Science v. 340, 2013
Recent technological advances in molecular genetics, molecular and cellular immunology, structural biology, bioinformatics, computational biology, nanotechnology, formulation methods, and systems biology are ushering in a new era of discovery. However, translation of these advances into vaccines remains impeded by major gaps in our knowledge of human immune responses.
Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer
K. Weiskoff et al. ScienceExpress May 31, 2013
AntibodiesCD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with approximately 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This “one-two punch” directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.