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Anti-mct1 antibodies and uses thereof

A technology of antibodies and antigens, applied to fusion or multispecific proteins, compositions containing such antibodies and antigen-binding fragments thereof, multispecific and bispecific antibodies, therapeutic and diagnostic uses, antagonistic anti-MCT1 antibodies and In the field of antigen-binding fragments, it can solve problems such as antibodies that have not yet been reported

Pending Publication Date: 2020-10-09
IMMUNEXT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to date, no antibodies that bind surface-expressed MCT1 have been reported, e.g., on the surface of human or non-human cells endogenously or engineered to express MCT1
Furthermore, to the applicant's knowledge, there are no literature reports of functional antibodies, i.e. those that bind to MCT1 to antagonize, inhibit or block the action of MCT1

Method used

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  • Anti-mct1 antibodies and uses thereof
  • Anti-mct1 antibodies and uses thereof
  • Anti-mct1 antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0637] Example 1. Differential expression of MCTs on T cells.

[0638] Materials and methods

[0639] The commercially available SM compound AZ3965 (MedChem Express, NJ) and related analogs were used to help uncover the unique biology of the MCT1 pathway in immune cells. For clarity, we will collectively refer to AZ3965 and its analogs with the same binding affinity, PK and MCT1 / 2 selectivity as "AZ3965".

[0640] Expression of MCT1, MCT2, MCT4 and BSG (CD147) was measured in unstimulated and stimulated leukocytes from two different donors. For "stimulated" conditions, cells were activated with CD3 / CD28 for 3 days. AZ3965 was tested for inhibition of stimulated cell proliferation.

[0641] result

[0642] MCT1 promotes the transfer of metabolites, including products of glycolysis, which are more important in activated T / B cells ( figure 1 ). figure 2 The expression levels of MCT1, MCT2, MCT4 and BSG (CD147) are shown in the two donors, demonstrating that activated T ...

Embodiment 2

[0644] Example 2: Validation of the feasibility of targeting MCT1 in vitro and in vivo for inflammatory / autoimmune disorders using the AZ3965 inhibitor.

[0645] in vitro

[0646] Effects on lactate transport. AZ3965 inhibited human T cells (CD4 + and CD8 + both), B-cell lymphoma (Daudi) and lactate transport in PBMCs, but not in monocytes ( image 3). AZ3965 inhibits lactate transport by up to 80% in affected cells, but does not affect transport in monocytes, which is important for protecting the innate immune response in treated individuals.

[0647] Human T cell proliferation. Administration of MCT1 inhibitor with an IC of 0.54 nM in a human T cell proliferation assay 50 Reduce T cell proliferation ( Figure 4 ).

[0648] Human mixed lymphocyte reaction (MLR). Administration of the MCT1 inhibitor with an IC of 1.34 nM in the human MLR assay 50 Reduce T cell proliferation ( Figure 5 ).

[0649] T cell cytokine secretion. T cells were activated by CD3 / CD28 in ...

Embodiment 3

[0658] Example 3: Development and binding characterization of anti-human MCT1 antibodies

[0659] Selection of MCT1 Ab1 mAbs. MCT1 Ab1 is a rat anti-human MCT1 monoclonal antibody selected after cell-based rodent immunization and binding screening using MCT1 expressing and MCT1 knockout (KO) cell lines.

[0660] Binding affinity and MCT1 cross-reactivity. Kinetic exclusion assay (KinExA) analysis showed that MCT1 Ab1 binds to human MCT1 with a Kd of 6.3 nM. MCT1 Ab1 is also highly cross-reactive with cynomolgus monkey (cyno) and rabbit MCT1, but not rodent MCT1 ( Figure 12A -D).

[0661] specificity of binding. HEK-293WT cells only expressed MCT1 / CD147, but no other MCTs, as determined by RT-PCR. To measure the binding specificity of the antibodies of the invention, the HEK-293MCT1 / CD147 double knockout cell line can be used as a negative control. In addition, this double knockout cell line was engineered to express individual transporters (MCT1, MCT2, MCT3, MCT4, CD147...

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Abstract

This invention generally pertains to antibodies and antigen-binding fragments thereof, e.g., humanized, chimeric, and human antibodies and antigen-binding fragments thereof, and fusion proteins, compositions containing such antibodies and antigen-binding fragments thereof and fusion proteins, wherein such antibodies and antigen-binding fragments thereof and fusion proteins specifically bind to MCT1, e.g., human or non-human MCT1 and antagonize, inhibit or block one or more MCT1-associated functions in vitro and / or in vivo. The invention also relates to therapeutic and diagnostic uses of theseanti-MCT1 antibodies, antigen-binding fragments, fusion proteins and compositions containing optionally wherein these anti-MCT1 antibodies, antigen-binding fragments, fusion proteins and compositionscontaining are used in therapeutic regimens that further include the administration of other therapeutic agents, e.g., mitochondrial inhibitors and / or biguanides or small molecule MCT1 inhibitors.

Description

[0001] Related applications [0002] This application claims U.S. Provisional Application No. 62 / 613,447, filed January 4, 2018, U.S. Provisional Application No. 62 / 684,870, filed June 14, 2018, and U.S. Provisional Application No. , filed September 25, 2018. 62 / 736,025 and priority to US Provisional Application No. 62 / 773,630, filed November 30, 2018. The contents of each of these provisional applications are incorporated herein by reference in their entirety. [0003] sequence listing [0004] Sequence Listing in a file named "43260.4213.txt" of size xxxxxx bytes created on January 4, 2019, incorporated herein by reference in its entirety. [0005] Field of Invention [0006] The present invention generally relates to anti-MCT1 antibodies and antigen-binding fragments thereof, eg, humanized, chimeric, and human antibodies, and antigen-binding fragments thereof, eg, antagonistic anti-MCT1 antibodies and antigen-binding fragments thereof, and containing such Compositions of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28G01N33/50
CPCC07K16/28C07K2317/76C07K2317/569A61K2039/505C07K2317/56C07K2317/30G01N33/577C07K2317/565A61P37/02C07K2317/92C07K2317/33C07K2317/24A61P37/06C07K16/40A61K47/68G01N33/5011A61K45/06A61P3/10A61P35/00G01N33/574
Inventor J·罗斯坦C·卡里尔S·谢廖金P·戈贝伊G·K·J·李K·P·希格纳卡M·戈登K·库翁Y·王R·D·莱威J·K·王R·钱伯斯D·F·塔克B·A·斯克伦奇
Owner IMMUNEXT INC