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Compositions and methods of enhancing Anti-tumor response using hybrid neutrophils

a technology of hybrid neutrophils and anti-tumor cells, which is applied in the field of compositions and methods of enhancing anti-tumor responses using hybrid neutrophils, can solve the problems of poor clinical efficacy of many therapeutic antibodies, limited therapeutic effects in trials, and the need for improvement of neutrophil-mediated ab therapy

Inactive Publication Date: 2018-09-06
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a method to make antibodies against tumors more effective. The method involves giving the subject the antibodies and a specific type of immune cell called a hybrid neutrophil. This hybrid neutrophil has certain molecules on its surface that make it better at fighting tumors. This method makes the antibodies more effective in treating tumors in the subject.

Problems solved by technology

Unfortunately, the clinical efficacy of many therapeutic antibodies is poor and needs to be enhanced (Liu et al., Cancer Chemother Pharmacol.
However, these trials only showed limited therapeutic effects, indicating that improvement of neutrophil-mediated Ab therapy is required.

Method used

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  • Compositions and methods of enhancing Anti-tumor response using hybrid neutrophils
  • Compositions and methods of enhancing Anti-tumor response using hybrid neutrophils
  • Compositions and methods of enhancing Anti-tumor response using hybrid neutrophils

Examples

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Effect test

example 1

Identification of a Novel Subset of Tumor-Associated Neutrophils (TANs) Exhibiting the Composite Characteristics of Neutrophils and Antigen-Presenting Cells

[0202]Characterization of tumor-associated neutrophils (TANs) revealed that the majority of TANs in early stage of non-small cell lung cancer (NSCLC) express classic neutrophil markers CD11b+CD15hiCD66b+MPO+Arg1+ (“canonical TANs”, FIG. 1B, boxes in lower left corner). However, another subpopulation of TANs that displayed a combination of neutrophil (Arg1+MPO+CD66b+CD15+) and antigen-presenting cell (APC) (CD14+HLA-DR+CCR7−CD86+) markers was identified. This subpopulation of TANs is hereinafter referred to as “hybrid TANs” or “hybrid tumor-associated neutrophils.” (FIG. 1B, boxes in upper right corner). The frequency of these newly identified “hybrid” subset of TANs varied widely in tumor tissues of cancer patients (FIG. 1C).

example 2

Identification of Conditions in which the Immature Bone Marrow or Peripheral Blood Granulocytes Could be Differentiated into Hybrid Neutrophils in a Large Numbers

[0203]Using anti-CD15 magnetic beads, a highly enriched population of human bone marrow neutrophils (BMNs) was obtained from rib fragments that were removed from patients during routine lung cancer surgery. It was found that these BMNs exhibited a prolonged survival in vitro compared to peripheral blood neutrophils (PBNs). These CD15+ BMNs expressed the myeloid / granulocytic specific markers CD11b, CD66b, Arg1, myeloperoxidase (MPO) and were mostly “band”-like immature neutrophils (FIG. 2A; FIG. 2C). Importantly, unlike blood, about 40% of these BMNs could survive in cell culture for up to 1 week (FIG. 2B). Thus, human BMNs have a prolonged lifespan in vitro, providing large quantities of cells (>50 million cells) that can be used to differentiate immature neutrophils into the hybrid neutrophils.

[0204]Several ways to differe...

example 3

Hybrid CD14+HLA-DR+CD32hiCD64hi CD89hi Neutrophils Efficiently Phagocytose Bacteria and Mediate a High Level of Antibody Dependent Phagocytosis (ADP).

[0211]CD32hiCD64hi CD89hi hybrid neutrophils (which could be generated in large numbers from immature bone marrow or peripheral blood) are powerful effector cells that trigger sufficient removal of tumor cells or infectious pathogens through ADP or ADCC. The support for this claim comes from a comparative analysis of canonical and hybrid neutrophils that revealed that hybrid neutrophils are characterized by (1) augmented ability to phagocytose bacteria (FIG. 5A); (2) expression of very high levels of FcγRI (CD64), FcγRII (CD32) and FcαR (CD89) (FIG. 5D) (of note, the high affinity FcγRI / CD64 represents the most potent neutrophil FcγR for induction of ADCC (Valerius et al., Blood. 1993 Aug. 1; 82(3): 931-939)); (3) increased ability to mediate the high level of antibody-dependent phagocytosis (FIG. 5B); and (4) ability to mediate ADCC (...

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Abstract

The present invention relates to compositions and methods that provide novel anti-tumor therapies in cancer. In one aspect, the present invention features a hybrid neutrophil in a non-naturally occurring container, wherein the hybrid neutrophil expresses at least one neutrophil associated molecule selected from the group consisting of: Arg1, MPO, CD66b, and CD15, and at least one antigen-presenting cell (APC) associated molecule selected from the group consisting of: CD14, HLA-DR, CD32, CD64, and CD89. In another aspect, the present invention features methods of generating a hybrid neutrophil. In still another aspect, the present invention features methods of inhibiting tumor growth in a subject, treating a tumor in a subject, and increasing efficacy of an antibody against a tumor in a subject. The methods comprise (a) administering to the subject an effective amount of an anti-tumor antibody and (b) administering to or generating in the subject an effective amount of a hybrid neutrophil.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 212,279, filed Aug. 31, 2015, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under grant number CA187392-01A1 NIH / NCI and awarded by LC140199 awarded by The Department of Defense. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Neutrophils are antimicrobial effector cells equipped with powerful killing machinery to respond to pathogens, especially to opsonized bacteria. It is thought that therapeutic antibodies against tumor antigens can direct and activate this cytotoxic machinery against opsonized tumor cells through Fc receptors, a process that is referred to as antibody-dependent cellular cytotoxicity (ADCC) (Musolino et al., J Clin Oncol. 2008; 26(11): 1789-1796; ...

Claims

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Application Information

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IPC IPC(8): A61K35/15A61K38/19A61P35/00A61K38/21A61K39/00A61K45/06A61K39/395
CPCA61K35/15A61K38/193A61P35/00A61K38/217A61K39/0011A61K45/06A61K39/39541A61K2300/00A61K2039/5158A61K2039/572A61K2039/585A61K31/454C12N5/0642C12N2501/22C12N2501/24C12N2501/599C12N2502/30A61K39/461A61K39/4622A61K2239/55A61K39/464488
Inventor ERUSLANOV, EVGENIYALBELDA, STEVEN
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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