In:
Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2729-2729
Abstract:
Antibody-dependent phagocytosis is a crucial mechanism underlying the efficacy of therapeutic antibodies for cancer. However, a major barrier to phagocytosis exists in the CD47-SIRPa interaction. CD47, a molecular “don’t eat me” signal, is highly expressed on many types of cancer and acts as a myeloid-specific immune checkpoint. By engaging SIRPa, an inhibitory receptor on macrophages, CD47 limits the ability of macrophages to respond to therapeutic antibodies. In this study, we developed anti-human SIRPa antibodies that block the interaction between CD47 and SIRPa. By themselves, these antibodies were not sufficient to induce human macrophage phagocytosis. However, when combined with a variety of tumor-specific antibodies, the anti-SIRPa antibodies exhibited remarkable synergy and augmented antibody-dependent phagocytosis of human cancer cells. Addition of anti-SIRPa antibodies improved phagocytosis of cancer in response to rituximab, cetuximab, and trastuzumab, among other therapeutic antibodies. Moreover, anti-SIRPa antibodies enhanced macrophage phagocytosis of lymphoma cells in response to anti-CD20 variants produced with each subclass of human IgG or glycoengineered anti-CD20 antibodies, indicating they could be effective for the majority of therapeutic antibodies that are clinically approved or under development. Importantly, both polarized macrophages and primary tumor-associated macrophages exhibited increased responses to therapeutic antibodies when SIRPa was blocked. In contrast to therapies targeting CD47 directly, anti-SIRPa antibodies benefit from more restricted expression of SIRPa and could have more favorable pharmacokinetic and toxicity profiles. They are an important addition to the growing arsenal of therapeutics targeting the CD47-SIRPa axis for cancer and could act as universal adjuvants to therapeutic antibodies. Disclosures Weiskopf: Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Ring:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Guo:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Volkmer:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Weissman:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V124.21.2729.2729
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2014
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
