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Hybrid antibodies

A technology of antibody and receptor, applied in the field of hybrid IgE antibody

Pending Publication Date: 2022-07-15
艾普西洛根有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, this is the biggest concern with the use of IgE-based immunotherapy against cancer: there is always a risk of anaphylaxis with intravenously administered recombinant IgE

Method used

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example

[0113] Functionally similar amino acids that can be exchanged by conservative substitutions are well known to those of ordinary skill in the art. The following six groups are examples of amino acids that are considered conservative substitutions for each other: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), glutamic acid ( E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L) ), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W).

[0114] The domains described above (eg, one or more IgE and IgG constant domains) are typically present in the heavy chains of antibodies. In addition to one or more heavy chain sequences as described herein, a hybrid antibody may also comprise one or more light chains. For example, in one embodiment, a hybrid antibody may comprise a light chain sequence as defined by SEQ ID NO:35, or a fragment or variant thereof. Antibodies are usually composed of heavy an...

Embodiment 1-Fc

[0140] Example 1 - FcRn constructs

[0141] IgE variants were created in which point mutations were made in loops found in the Cε3 and Cε4 domains of IgE. These mutations replaced original amino acids with histidines at positions known to be involved in IgG-FcRn interactions. IgE antibodies are based on trastuzumab IgE, eg as Karagiannis et al. (2009) Cancer Immunol. Immunother. 58 (6): disclosed in 915-30.

[0142]Additional variant IgE antibodies were generated in which loops in the Cε3 and Cg4 domains of IgE were replaced by one or more FcRn binding loops derived from the Cγ2 and Cγ3 domains of IgG antibodies. The loops that are replaced in the Cg3 and Cε4 domains of IgE show structural homology to the FcRn binding loops in the Cγ2 and Cγ3 domains of IgG.

[0143] For comparison, two IgE fusion constructs were created in which i) the IgG-derived hinge and Cγ2 domains were fused to the C-terminus of trastuzumab IgE, and ii) the IgG hinge and Cγ2 and Cγ3 domains were fus...

Embodiment 2-I

[0231] Example 2 - Binding of IgE variants to FcRn

[0232] To assess the binding of antibody variants to FcRn (Sino Biological Cat. No. CT009-H08H), single concentration Biacore kinetic analysis was performed on supernatants from transfected CHO cell cultures. Kinetic experiments were performed on a Biacore T200 (serial number 1909913) running Biacore T200 Control software V2.0.1 and Evaluation software V3.0 (GE Healthcare, Uppsala, Sweden). The measurement principle is as figure 1 shown. All kinetic experiments were performed at 25°C using PBS containing 0.05% P20 (GE Healthcare, Little Chalfont, UK) and an additional 150 mM NaCl (pH 6.0). Antibodies were loaded on F of a Straptavidin chip (GE Healthcare, Little Chalfont, UK) preloaded with CaptureSelect biotin anti-IgE (Thermo cat no. 7103542500). c 2. F c 3 and F c 4 on. Antibody was captured at a flow rate of 10 μl / min to give a fixed level (RL) of ~250RU. Binding data were acquired using FcRn at 2000 nM at a flo...

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Abstract

Described herein are hybrid antibodies targeted for the treatment of cancer. The antibodies have binding ability to Fc epsilon receptor and neonatal Fc receptor, which can be achieved, for example, by replacing the sequence or amino acid in the IgE constant domain with the corresponding sequence and amino acid derived from IgG.

Description

[0001] Field of Invention [0002] The present invention resides in the design of synthetic (non-naturally occurring) hybrid antibodies, particularly hybrid IgE antibodies, and their therapeutic use. [0003] Background of the Invention [0004] Immunoglobulin E (IgE) is a class of antibodies (or immunoglobulin (Ig) "subtype") found only in mammals. IgE is synthesized by plasma cells. As with all antibody classes, the monomer of IgE consists of two larger identical heavy chains (epsilon chains) and two identical light chains (which are common to all antibody classes), where the epsilon chains contain four Ig-like constants Domain (Cε1-Cε4). [0005] What distinguishes the different antibody classes is the nature of the heavy chains, wherein the heavy chains of the IgE class are larger and more glycosylated than those of the more common IgG class. Each antibody chain consists of a series of immunoglobulin domains arranged in tandem. The N-terminal domains (one each for the l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K16/00C07K16/30C07K16/32
CPCA61P35/00C07K16/00C07K2317/52C07K2317/524C07K2317/526C07K2317/528C07K16/32C07K2317/732C07K2317/66C07K2319/00C07K2317/72C07K16/3053C07K16/283A61K2039/505C07K2317/24C07K2317/92C07K16/30C07K2317/53
Inventor T·威尔逊K·菲茨杰拉德
Owner 艾普西洛根有限公司
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