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Antibodies targeting glycoprotein vi

An antibody and antibody fragment technology, applied in the direction of antibodies, immunoglobulins, antibody medical components, etc., can solve problems such as lack of cross-reactivity

Pending Publication Date: 2020-12-22
MORFOZIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this antibody is a humanized form of the earlier published antibody 9012.2 (see WO2001000810) and thus lacks cross-reactivity with rodent GPVI, a commonly used relevant model for in vivo studies
In addition, ACT-017 has a risk of being recognized by anti-Fab antibodies in patient sera due to its structure at the C-terminus of the Fab heavy chain
This immune response may lead to undesired restoration of bivalent GPVI binding and GPVI activation in platelets

Method used

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  • Antibodies targeting glycoprotein vi
  • Antibodies targeting glycoprotein vi
  • Antibodies targeting glycoprotein vi

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0107] sequence

[0108] In one embodiment, the present disclosure relates to antibodies or antibody fragments specific for glycoprotein VI (GPVI). In one embodiment, the present disclosure relates to isolated antibodies or antibody fragments specific for glycoprotein VI (GPVI). In one embodiment, the present disclosure relates to isolated monoclonal antibodies or antibody fragments specific for GPVI. In one embodiment, the present disclosure relates to an isolated monoclonal antibody or antibody fragment specific for GPVI comprising the variable heavy chain (VH) and variable light chain (VH) of any one of the antibodies disclosed in Tables 1-4 VL), in one embodiment, the present disclosure relates to an isolated monoclonal antibody or antibody fragment specific for GPVI comprising the heavy chain (HC) and light chain (LC) of any one of the antibodies disclosed in Tables 1-4 ).

[0109] In one embodiment, the present disclosure relates to an isolated monoclonal antibody or ...

Embodiment 13

[0493] Thus, in one embodiment, a Fab specific for GPVI of the present disclosure does not substantially activate platelets due to recognition by anti-Fab antibodies present in the subject's serum. In another embodiment, the Fabs of the disclosure specific for GPVI do not substantially induce the expression of cell surface activation markers such as CD62P on platelets.

[0494] The inventors of the present application have confirmed that modification of the C-terminus of the Fab heavy chain can further reduce, prevent or inhibit the possibility of this Fab-induced platelet activation, for example by preventing the anti-Fab antibodies present in the subject's serum from recognizing the GPVI-specific Fab.

[0495] Herein, "prevent recognition" or "prevent binding" means that the Fabs specific for GPVI of the present disclosure do not cross-link GPVI on the platelet surface and activate GPVI signaling due to the presence of anti-Fab antibodies in the subject's serum. This cross-...

Embodiment 1

[0667] Example 1: Antigen Production and Quality Control

[0668] The amino acid sequences of GPVI for human, cynomolgus monkey, mouse and rat were retrieved from publicly available sources (eg Uniprot) and produced in-house.

[0669] recombinant soluble extracellular domain

[0670] Soluble GPVI corresponds to the extracellular domain of GPVI fused at its C-terminus to a human Fc sequence. This soluble GPVI can be referred to as GPVI-Fc.

[0671] Human GPVI-1A (SEQ ID NO: 4), human GPVI-1B (SEQ ID NO: 5), human GPVI-2A (SEQ ID NO: 6), cynomolgus monkey GPVI (SEQ ID NO: 7), mouse The extracellular domain (ECD) of GPVI (SEQ ID NO: 8) and rat GPVI (SEQ ID NO: 9) was cloned into the expression vector pMAX_vk_Fc2 (K105-K330) using KpnI and EcoRV to generate the C-terminal Fc2 (K105- K330) fusion construct. Fc2(K105-K330) has the amino acid sequence disclosed in SEQ ID NO:10.

[0672] The DNA encoding the extracellular domain of human, cynomolgus monkey, mouse or rat GPVI wa...

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Abstract

The present disclosure provides antibodies or antibody fragments specific for GPVI. In particular, it relates to antibodies or antibody fragments that have combined beneficial properties and are therefore useful for the treatment or prophylaxis of GPVI related disorders or conditions, such as for example thrombotic or vascular disorders.

Description

technical field [0001] The present application relates to antibodies or antibody fragments (eg Fab) that bind glycoprotein VI (GPVI). The present disclosure also relates to nucleic acids, vectors and host cells capable of expressing the antibodies or antibody fragments, pharmaceutical compositions comprising the antibodies or antibody fragments, and uses of the antibodies or antibody fragments for the treatment of specific diseases. Background technique [0002] Platelet activation is critical in the development of arterial thrombosis and cardiovascular disorders. Patients with these conditions are often treated with antiplatelet drugs that interfere with thrombus formation by targeting late events in the process. A serious side effect of these drugs is prolonged bleeding, which limits their use. [0003] GPVI is a major collagen receptor expressed only on platelets and megakaryocytes. Binding of GPVI to collagen, one of the most important thrombogenic components of the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/28A61P9/10
CPCC07K16/2803C07K2317/21C07K2317/33C07K2317/76C07K2317/92A61K39/39533A61K2039/505A61P9/10A61P9/00C07K2317/565C07K2317/24C07K2317/30C07K2317/55A61P7/02
Inventor K·乌兰J·诺伊格鲍尔S·伦滋
Owner MORFOZIS AG
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