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Anti-galectin-1 (GAL1) monoclonal antibodies and fragments thereof for neutralizing gal1

a monoclonal antibody and anti-gal1 technology, applied in the field of anti-gal1 (gal1) monoclonal antibodies and fragments thereof, can solve the problems of poor event-free survival and little evidence of an effective host anti-tumor immune response, and achieve the effect of preventing or delaying the ons

Inactive Publication Date: 2016-07-28
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]In yet another aspect, a method for preventing or delaying the onset of, or slowing the rate of progression of, a disease in a subject mediated by Gal1 activity, comprising administering to the subject a prophylactically or therapeutically effective amount of an agent selected from the group consisting of a polypeptide of the present invention described herein, a nucleic acid of the present invention described herein, a vector of the present invention described herein, a host cell of the present invention described herein, an immunogenic composition of the present invention described herein, or an antibody of the present invention described herein, thereby preventing or delaying the onset of, or slowing the rate of progression of, the Gal1-mediated disease in the subject, is provided.

Problems solved by technology

Although primary cHLs have a brisk inflammatory infiltrate, there is little evidence of an effective host antitumor immune response.
Increased Gal1 expression in immunohistochemical analyses of primary cHLs is associated with poorer event-free survival (Kamper et al.

Method used

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  • Anti-galectin-1 (GAL1) monoclonal antibodies and fragments thereof for neutralizing gal1
  • Anti-galectin-1 (GAL1) monoclonal antibodies and fragments thereof for neutralizing gal1
  • Anti-galectin-1 (GAL1) monoclonal antibodies and fragments thereof for neutralizing gal1

Examples

Experimental program
Comparison scheme
Effect test

example 1

Neutralizing Anti-Gal1 Monoclonal Antibodies Useful for Therapeutic Applications

[0259]Neutralizing anti-Gal1 monoclonal antibodies were generated and reacted with human recombinant Gal1 and endogenous Gal1 in biochemical assays and in immunohistochemical analyses of primary tumors. In addition, several of the Gal1 monoclonal antibodies also cross-reacted well with endogenous Gal1 from cynomologous monkey and mouse (FIG. 1). Epitope mapping indicated that the 8B5, 8F4 and 8G3 Gal1 monoclonal antibodies all recognized a domain distal to the previously described carbohydrate-binding domain (FIG. 2 and Table 1).

[0260]These antibodies (i.e., 8B5, 8F4, and 8G3) were subsequently sequenced and determined to each have the same sequence, with the light chain being lambda. Briefly, total RNA was extracted from each hybridoma and subjected to RT-PCR using constant region specific 3′ primers and pools of degenerate signal sequence specific 5′ primers. Amplified products were cloned and sequence...

example 2

Fine Epitope Mapping of Neutralizing Anti-Gal1 Monoclonal Antibodies Useful for Therapeutic Applications

[0262]The 8F4 mAb was determined to cross-react well with both human Gal1 and mouse Gal1 in FIG. 1 and recognize a post-CBD domain of Gal1 in Table 2 were further subjected to fine epitope mapping analyses. In addition to the seven GST-tagged human Gal1 constructs shown in FIG. 2 and produced in E. coli, five additional 6×HIS-tagged human Gal1 constructs spanning various portions of the human Gal1 polypeptide were generated in E. coli for use in epitope mapping analyses (FIG. 2). FIG. 2 further demonstrates how the amino acids encompassed by each GST-tagged and HIS-tagged construct maps with respect to the β-strands in the five-stranded β-sheets (F1-F5) and six-stranded β-sheets (S1-S6a / S6b) of the folded human Gal-1 polypeptide (FIG. 3). The Gal1-neutralizing 8F4 mAb was determined to recognize recombinant HIS-F7, HIS-F5, and HIS-F9 by Western blot analysis, whereas an anti-Gal1,...

example 3

Biophysical Properties of Neutralizing Anti-Gal1 Monoclonal Antibodies Useful for Therapeutic Applications

[0263]Surface Plasmon Resonance (SPR) analyses (also called Biomolecular Interaction Analysis, BIAcore) were also conducted in order to further define the biophysical properties (e.g., kon, koff, koff / kon, (KD) of Gal1's interaction with the 8F4 mAb. SPR experiments were performed at 25° C. in the standard BIAcore running buffer HBS-EP on a BIAcore 3000) Instrument (BIAcore). In brief, anti-mouse antibody was first captured on the CM-5 sensor chip (GE HealthCare). Afterwards, approximately 250 response units (RU) of the 8F4 anti-Gal1 mAb were immobilized (with exception of ˜350 RU for rmGal1 assay) and followed by various dilutions of recombinant galectin (human galetin-1,2, 3, 4, 7, 8, 9 or murine galectin-1 (mGal1), from R&D Systems) to assess the binding of galectin to 8F4. All data are shown after subtraction from a channel loaded with buffer alone. Data analysis to obtain t...

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Abstract

The present invention is based, in part, on the discovery of galectin 1 (Gal1) epitopes against which anti-Gal1 agents can neutralize Gal1 function, as well as anti-Gal1 agents and methods useful for neutralizing Gal1 function.

Description

BACKGROUND OF THE PRESENT INVENTION[0001]Galectin-1 (Gal1), a member of a highly conserved family of carbohydrate-binding proteins, modulates immune responses and fosters tumor-immune escape through specific recognition of N-acetyllactosamine (Gal-β1-4-NAcGlc) residues on the branches of N- or O-linked glycans (Juszczynski et al. (2007) Proc Natl Acad Sci USA. 104:13134-13139; Rabinovich and Croci (2012) Immunity 36:322-335; Rabinovich and Toscano (2009) Nat. Rev Immunol. 9:338-352; Rubinstein et al (2004) Cancer Cell 5:241-251).[0002]Gal1 selectively induces the apoptosis of cytotoxic T cells and T helper (Th) 1 and Th17 cells by interacting with specifically sialated cell surface glycoproteins, such as CD45, CD43 and CD7 (Toscano et al. (2007) Nat. Immunol. 8:825-834). Since Th2 cells and regulatory T (Treg) cells lack the Gal1-binding glycoprotein motif, Gal1 spares these cells and fosters an immunosuppressive Th2 / Treg-enriched tumor microenvironment (Toscano et al (2007) Nat. Im...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28G01N33/68A61K39/00
CPCC07K16/2851A61K39/0005G01N33/6854A61K2039/505C07K2317/33C07K2317/565C07K2317/34C07K2317/76G01N33/57484C07K2317/70C07K2317/92A61P35/00A61P37/02C07K16/18G01N33/577
Inventor SHIPP, MARGARET A.OUYANG, JINGRODIG, SCOTT J.
Owner DANA FARBER CANCER INST INC
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