Publication Date:
2013-06-01
Description:
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPalpha, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPalpha variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPalpha. As high-affinity SIRPalpha 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810306/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Weiskopf, Kipp -- Ring, Aaron M -- Ho, Chia Chi M -- Volkmer, Jens-Peter -- Levin, Aron M -- Volkmer, Anne Kathrin -- Ozkan, Engin -- Fernhoff, Nathaniel B -- van de Rijn, Matt -- Weissman, Irving L -- Garcia, K Christopher -- CA139490/CA/NCI NIH HHS/ -- F30 CA168059/CA/NCI NIH HHS/ -- F30 DK094541/DK/NIDDK NIH HHS/ -- F30CA168059/CA/NCI NIH HHS/ -- F30DK094541/DK/NIDDK NIH HHS/ -- GM07365/GM/NIGMS NIH HHS/ -- P01 CA139490/CA/NCI NIH HHS/ -- P30 CA124435/CA/NCI NIH HHS/ -- R01 CA086017/CA/NCI NIH HHS/ -- R01 CA112270/CA/NCI NIH HHS/ -- R01 CA177684/CA/NCI NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 5;341(6141):88-91. doi: 10.1126/science.1238856. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722425" target="_blank"〉PubMed〈/a〉
Keywords:
*Adjuvants, Immunologic
;
Animals
;
Antibodies, Monoclonal/*therapeutic use
;
Antibodies, Monoclonal, Murine-Derived/therapeutic use
;
Antibodies, Neoplasm/*therapeutic use
;
Antigens, CD47/*immunology
;
Antigens, Differentiation/chemistry/genetics/*therapeutic use
;
Cell Line, Tumor
;
Directed Molecular Evolution
;
Humans
;
Immunotherapy
;
Macrophage Activation
;
Mice
;
Neoplasms/immunology/*therapy
;
Phagocytosis
;
Receptors, Immunologic/chemistry/genetics/*therapeutic use
;
Rituximab
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
