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Compositions and methods using humanized Anti-dkk2 antibodies

A technology of humanization and composition, applied in chemical instruments and methods, biochemical equipment and methods, antibodies, etc.

Pending Publication Date: 2022-04-05
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the interaction of Dkk with Kremen (also a transmembrane protein) was shown to promote Dkk antagonism of Wnt signaling, this interaction may have other unresolved functions

Method used

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  • Compositions and methods using humanized Anti-dkk2 antibodies
  • Compositions and methods using humanized Anti-dkk2 antibodies
  • Compositions and methods using humanized Anti-dkk2 antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0323] Example 1: Generation of Humanized Anti-DKK2 Antibodies

[0324] image 3 The amino acid and nucleic acid sequences of the mouse anti-DKK2 5F8 monoclonal antibody (5F8 mAb) (light chain (SEQ ID NO: 5 and 6) and heavy chain (SEQ ID NO: 7 and 8)) are listed.

[0325] Figure 4 Nucleic acid sequences and enzymes used to synthesize humanized anti-DKK2 antibodies are listed. The enzymes Kpn I and Xho I are used for the light chain (SEQ ID NO:9), and the enzymes Kpn I and Age I are used for the heavy chain (SEQ ID NO:10).

[0326] Such as Figure 5 and 6 As shown, successful ligation occurred between expression vector pJH16-hIgK and clone YAL008-5F8-VL and between expression vector pJH16-hIG1 and clone YAL008-5F8-VH.

[0327] ELISA results of YAL008 5F8 chimeric expression results are shown in Figures 7A-7B middle.

[0328] Figure 8 and Figure 9 The light chain and heavy chain amino acid sequences (SEQ ID NO: 11-29) of various clones of humanized anti-DKK2 antib...

Embodiment 2

[0333] Example 2: Summary of humanized anti-DKK2 antibodies.

[0334] DKK2 is secreted and is a suitable candidate to be targeted with antibodies (Abs) to reduce tumor burden. A mouse antibody clone (5F8) with high specificity for DKK2 was previously developed, which neutralizes DKK2 and inhibits its Wnt antagonist function. A humanized antibody carrying CDRs similar to 5F8 was generated here. The nucleic acid sequence and amino acid sequence of the humanized anti-DKK2 antibody of the present invention are listed in figure 1 and figure 2 middle.

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Abstract

Provided herein are the discovery that inhibition of Dickkopf2 (DKK2) increases CD8 + cytotoxic T lymphocyte (CTL) activity, attenuates tumors, and thereby inhibits tumor formation. Thus, in various embodiments described herein, the methods of the invention relate to methods of treating cancer by administering to a patient an effective amount of a humanized anti-DKK2 antibody, methods of providing anti-tumor immunity in a subject, methods of stimulating a T cell mediated immune response against a population of cells or tissues, and inhibiting tumors in a subject. In addition, provided herein are methods including diagnosing cancer or a predisposition to develop cancer or metastasis, as well as methods of determining the use of an immunotherapy treatment or a cancer vaccine for the treatment of cancer. In addition, a pharmaceutical composition for treating cancer and a kit for carrying out the above method are provided.

Description

Background technique [0001] Cancer is a major health problem worldwide. Every year, tens of millions of people around the world are diagnosed with cancer, and more than half of these patients eventually die of cancer. About half of all men and one-third of all women in the United States will be diagnosed with cancer at some point in their lifetime, and one in four deaths is attributable to cancer (Jemal et al., CA Cancer J. Clin. , 2002, 52:23-47; Howlader et al., SEER Cancer Statistics Review, 1975-2010, National Cancer Institute). The most commonly identified human cancers include cancers arising from organs and solid tissues, eg, colon, lung, breast, stomach, prostate, and endometrial cancers. Colon cancer affects one in 20 people in the Western Hemisphere (Henderson, Nature Cell Biology, 2000, 2(9):p.653-60). Globally, 1 million new patients are diagnosed with colon cancer each year, and half of them die from the disease (Liu et al., Cell, 2002, 108(6):p.837-47). [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/18C07K16/00A61P35/00C12Q1/6886G01N33/68
CPCA61P35/00C07K16/18G01N2800/52G01N33/57484G01N2800/50C07K2317/24C07K2317/92C07K2317/76C07K16/2818C07K2317/565
Inventor L·孙
Owner YALE UNIV