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Therapeutic combinations comprising Anti-cd73 antibodies and uses thereof

Inactive Publication Date: 2016-05-12
MEDIMMUNE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides isolated binding molecules that specifically bind to CD7, which is a protein that is overexpressed in various types of cancer such as breast, colon, lung, and melanoma. These binding molecules can be antibodies or fragments thereof, and can be used to reduce tumor-mediated immunosuppression and improve overall survival and tumor-specific immune response. The invention also includes the use of an adenosine receptor inhibitor, called SCH58261, which further enhances the therapeutic effect of the binding molecules. In addition, the invention provides methods for treating CD7-overexpressing tumors and cancers with a prometastatic phenotype.

Problems solved by technology

Elevated CD73 expression has also been associated with tumor invasiveness, metastasis, and reduced patient survival time.

Method used

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  • Therapeutic combinations comprising Anti-cd73 antibodies and uses thereof
  • Therapeutic combinations comprising Anti-cd73 antibodies and uses thereof
  • Therapeutic combinations comprising Anti-cd73 antibodies and uses thereof

Examples

Experimental program
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Effect test

example 1

Isolation and Identification of Anti-CD73 Antibodies

[0333]Human scFv phage display libraries were panned with biotinylated CD73 extracellular domain (ECD) to isolate antibodies binding to human, cynomolgus, and murine CD73. CD73-specific scFv antibodies were isolated from the human scFv phage display library in a series of repeated alternate selection cycles on biotinylated human and murine CD73 extracellular domain (ECD) produced in-house from mammalian cells essentially as described previously in Lloyd et al., PEDS 22:159-68 (2009). ScFv genes from rounds 2 and 3 of the selection outputs were converted in batch into bacterial scFv-Fc or Fab expression vectors. Bacterial culture supernatants carrying soluble scFv-Fc or Fab were screened for their binding to human, murine, and cynomolgus CD73 ECD by ELISA or homogeneous time resolved fluorescence HTRF). The top hits showing cross reactivity were selected, subjected to DNA sequencing, and converted to whole immunoglobulin G1 triple m...

example 2

Epitope Binning of Anti-CD73 Antibodies

[0337]The ability of anti-CD73 antibodies to compete with each other for binding to human CD73 ECD was assessed on an Octet instrument essentially as described (Abdiche Y N et al., Anal Biochem 386: 172-80 (2009). CD73 ECD protein and first anti-CD73 antibody were pre-incubated and added to a biotinylated second anti-CD73 antibody captured on a Streptavidin sensor. If the first anti-CD73 antibody blocked binding of CD73 ECD to the second anti-CD73 antibody, both antibodies were placed in same or overlapping epitope bins. If both antibodies could bind simultaneously to CD73 ECD, they were placed in non-overlapping epitope bins. Pairwise testing of the anti-CD73 antibodies demonstrated that they belong to 3 non-overlapping epitope bins (Table 2).

TABLE 2Epitope bins of anti-CD73 antibodiesEpitope binAntibodiesACD730002, CD730004, CD730008, CD730011BCD730003, CD730010, CD730021, CD730042,CD730046, CD730047CCD730068, CD730069

example 3

Binding of Anti-CD73 Antibodies to CD73

[0338]The binding affinity and specificity of anti-CD73 antibodies was determined by Surface Plasmon Resonance (SPR) and flow cytometry.

[0339]A ProteOn XPR36 instrument was used to characterize binding of MEDI9447 to human, murine, and cynomolgus CD73 ECD. MEDI9447 was affinity-captured using an anti-human Fc antibody. CD73 ECD was in the mobile phase. The association and dissociation of CD73 to MEDI9447 could be accurately described with the Langmuir 1:1 model. The results shown in Table 3 demonstrate that the affinity of MEDI9447 to CD73 ECD from the three species is comparable and in the low picomolar range.

TABLE 3Affinity of MEDI9447 to CD73 ECD Determinedby Surface Plasmon ResonanceAnalyteka (M−1s−1)kd (s−1)KD (M)Human CD73 ECD2.57 × 1061.06 × 10−54.1 × 10−12Murine CD73 ECD2.41 × 1062.32 × 10−60.9 × 10−12Cynomolgus CD732.71 × 1061.76 × 10−56.5 × 10−12ECDka Association rate constant;kd Dissociation rate constant;KD Dissocation constant

[0340...

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Abstract

The present invention provides therapeutic combinations featuring anti-CD73 antibodies (e.g., MEDI9447) and A2A receptor inhibitors and methods of using such combinations for reducing tumor-mediated immunosuppression.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 078,243, filed Nov. 11, 2014, which is incorporated by reference herein in its entirety for all purposes.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 9, 2015, is named CD73-200US1_SL.txt and is 128,702 bytes in size.BACKGROUND OF THE INVENTION[0003]CD73 or ecto-5′nucleotidase (5′-NT) is ubiquitously expressed in a number of tissues. This protein is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) linkage, has ecto-enzyme activity, and plays a role in signal transduction. The primary function of CD73 is the conversion of extracellular nucleotides (e.g., 5′-AMP), to which cells are generally impermeable, to their corresponding nucleosides (e.g., aden...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/519
CPCA61K31/519A61K39/39558C07K16/2818C07K16/2896C07K16/40A61K2039/505A61K2039/507C07K2317/33C07K2317/622C07K2317/73C07K2317/76C07K2317/77C07K2317/92C07K2317/21A61P35/00A61P35/04A61P37/02A61P43/00A61K2300/00
Inventor SACHSENMEIER, KRISSULT, ERINHAY, CARLPOON, EDMUND
Owner MEDIMMUNE LTD
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