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Multispecific antigen-binding molecules and uses thereof

a multi-specific, antigen-binding technology, applied in the field of therapeutic proteins, can solve the problems of unintended side effects, high technical complexity of strategies, and interference with the normal biological activity of antigens, and achieve the effects of improving the therapeutic effect, and improving the therapeutic

Inactive Publication Date: 2013-09-19
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a novel strategy for inactivating or attenuating the activity of a target molecule without necessarily blocking its interaction with other molecules. This is achieved by facilitating a physical linkage between the target molecule and an internalizing effector protein, which then forces the target molecule into cells and processes it for degradation. This mechanism offers a more effective way to inactivate or attenuate the activity of a target molecule. The invention also provides a multispecific antigen-binding molecule that can simultaneously bind a target molecule and an internalizing effector protein, resulting in enhanced attenuation of the target molecule. The method of using the multispecific antigen-binding molecule to inactivate or attenuate the activity of a target molecule is also provided.

Problems solved by technology

For example, antibody-based therapeutics often function by binding to a particular antigen expressed on the surface of a cell, or to a soluble ligand, thereby interfering with the antigen's normal biological activity.
Although genetic and nucleic acid-based strategies for reducing the amount or concentration of a given target molecule are known in the art, such strategies are often fraught with substantial technical complications and unintended side effects in therapeutic settings.

Method used

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  • Multispecific antigen-binding molecules and uses thereof
  • Multispecific antigen-binding molecules and uses thereof
  • Multispecific antigen-binding molecules and uses thereof

Examples

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Effect test

example 1

Use of a Multispecific Antigen-Binding Molecule to Induce Degradation of a Cell Surface Receptor Via Linkage with an Internalizing Effector Protein

[0070]As an initial proof-of-concept experiment, a multispecific antigen-binding molecule was created which is capable of binding (a) an internalizing effector molecule and (b) a cell surface receptor target molecule. In this Example, the internalizing effector protein is Kremen-2 (Krm2), and the cell surface receptor target molecule is an Fc receptor (FcγR1 [Fc-gamma-R1]).

[0071]Kremen molecules (Krm1 and Krm2) are cell-surface proteins known to mediate WNT signaling by directing the internalization and degradation of the WNT pathway signaling molecules LRP5 and LRP6. Internalization of LRP5 / 6 is accomplished via the soluble interacting protein DKK1. In particular, DKK1 links Kremen to LRP5 / 6 on the cell surface, and because of this linkage, the internalization of Kremen drives the internalization and degradation of LRP5 and LRP6. (See Li...

example 2

IL-4R Activity is Attenuated Using a Multispecific Antigen-Binding Molecule with Specificity for IL-4R and CD63

[0077]In a further set of proof-of-concept experiments, a multispecific antigen-binding molecule was constructed which is capable of simultaneously binding a cell surface-expressed target molecule (i.e., IL-4R) and a cell surface-expressed internalizing effector protein (i.e., CD63). The purpose of these experiments was to determine whether IL-4R activity on a cell can be attenuated to a greater extent by physically linking IL-4R to an effector molecule that is internalized and targeted for degradation within the lysosome (in this case, CD63). In other words, this Example was designed to test whether the normal internalization and degradation of CD63 could be used to force the internalization and degradative rerouting of IL-4R within a cell.

[0078]First, a multispecific antigen-binding molecule was constructed that is able to bind both IL-4R and CD63. Specifically, a strepta...

example 3

An Anti-IL-4R×Anti-CD63 Bispecific Antibody Attenuates IL-4R Activity in a CD63-Dependent Manner

[0086]The experiments of Example 2, herein, show that an anti-IL-4R / anti-CD63 multispecific molecule inhibits IL-4-mediated signaling in a CD63-dependent manner. In those experiments, the multispecific antigen-binding molecule consisted of two separate monoclonal antibodies (anti-IL-4R and anti-CD63) that were connected via a biotin-streptavidin linkage. To confirm that the results observed with that proof-of-concept multispecific antigen-binding molecule are generalizable to other multispecific antigen-binding molecule formats, a true bispecific antibody was constructed.

[0087]Standard bispecific antibody technology was used to construct a bispecific antibody consisting of a first arm specific for IL-4R and a second arm specific for CD63. The IL-4R-specific arm contained an anti-IL-4R heavy chain paired with a CD63-specific light chain. The CD63-specific light chain was paired with the IL...

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Abstract

The present invention provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present invention can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the invention, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone. In other embodiments of the invention, the target molecule is a tumor associated antigen, and the simultaneous binding of the tumor associated antigen and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention causes or facilitates the targeted killing of tumor cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. provisional application Nos. 61 / 610,494, filed on Mar. 14, 2012; 61 / 721,831, filed on Nov. 2, 2012; and 61 / 751,286, filed on Jan. 11, 2013, the disclosures of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to the field of therapeutic proteins, and in particular, to the field of therapeutic proteins that are capable of inactivating, blocking, attenuating, eliminating and / or reducing the concentration of one or more target molecules in vitro or in vivo.BACKGROUND[0003]Therapeutic treatments often require the inactivation or blocking of one or more target molecules that act on or in the vicinity of a cell. For example, antibody-based therapeutics often function by binding to a particular antigen expressed on the surface of a cell, or to a soluble ligand, thereby interfering with the antigen's normal bi...

Claims

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Application Information

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IPC IPC(8): C07K16/28
CPCC07K16/1203C07K16/22C07K16/283C07K16/28C07K2317/77C07K16/2866C07K16/2896C07K2317/31C07K14/705A61P35/00A61P19/08A61K2039/505C07K16/30C07K16/2863C07K16/2851C07K16/2869C07K16/16C07K16/2833C07K14/70596C07K14/7155C07K14/475C07K2317/94A61K39/3955A61K47/6879A61K47/6817
Inventor PAPADOPOULOS, NICHOLAS J.MURPHY, ANDREW J.ECONOMIDES, ARIS N.CYGNAR, KATHERINE DIANA
Owner REGENERON PHARM INC
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