PDBsum entry 4kjy

Immune system

PDB id: 4kjy

Contents

Protein chains

114 a.a.

114 a.a.

Ligands

SO4 ×3

NAG ×8

Waters ×378

PDB id:

4kjy

Name:

Immune system

Title:

Complex of high-affinity sirp alpha variant fd6 with cd47

Structure:

Leukocyte surface antigen cd47. Chain: a, c. Synonym: antigenic surface determinant protein oa3, integrin- associated protein, iap, protein mer6. Engineered: yes. Mutation: yes. High-affinity sirpa variant fd6. Chain: b, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd47, mer6. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.93Å R-factor: 0.221 R-free: 0.262

Authors:

A.M.Ring,E.Ozkan,C.C.M.Ho,K.C.Garcia

Key ref:

K.Weiskopf et al. (2013). Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science, 341, 88-91. PubMed id: 23722425 DOI: 10.1126/science.1238856

Date:

04-May-13 Release date: 12-Jun-13

Protein chains

Q08722  (CD47_HUMAN) -  Leukocyte surface antigen CD47 from Homo sapiens

Seq: 323 a.a.

Struc: 114 a.a.*

Protein chains

No UniProt id for this chain

Struc: 114 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1126/science.1238856

Science 341:88-91 (2013)

PubMed id: 23722425

Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.

K.Weiskopf, A.M.Ring, C.C.Ho, J.P.Volkmer, A.M.Levin, A.K.Volkmer, E.Ozkan, N.B.Fernhoff, M.van de Rijn, I.L.Weissman, K.C.Garcia.

ABSTRACT

CD47 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 about a 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.