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Macropinocytosing human anti-CD46 antibodies and targeted cancer therapeutics

An antibody, human technology, applied in the direction of antibodies, chemical instruments and methods, anti-animal/human immunoglobulin, etc., can solve the problem of not providing the degree of specificity of cancer cells

Active Publication Date: 2017-09-05
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Although many antibodies have been discovered by this method, the screening process against cell lines does not provide a picture of how specific these antibodies are to the actual cancer cells in the patient population

Method used

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  • Macropinocytosing human anti-CD46 antibodies and targeted cancer therapeutics
  • Macropinocytosing human anti-CD46 antibodies and targeted cancer therapeutics
  • Macropinocytosing human anti-CD46 antibodies and targeted cancer therapeutics

Examples

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example

[0654] The following examples are offered to illustrate, not limit, the invention.

example 1

[0656] Novel anti-CD46 antibodies and uses thereof

[0657] To identify novel anti-human CD46 antibodies, a recombinant Fc fusion protein consisting of Sushi domains 1 and 2 of human CD46 was formed. Since the complementary sequence elements primarily bind to domains 3 and 4, the selection of domains 1 and 2 minimizes the selection of antibodies that might strongly interfere with standard complementary sequence function. This CD46-Fc fusion was made and purified from transfected HEK293 cells by protein A affinity chromatography. For human antibody selection, pooled cDNA from peripheral blood mononuclear cells of 426 healthy human donors was used to form 5 x 10 9 A phagemid display library of 2 members was selected, and the library was selected for recombinant CD46-Fc fusion proteins. After three rounds of selection, binding phagemids were screened by FACS and sequencing. Meanwhile, an alternative strategy was employed, which involved first selection of the library on live...

example 2

[0680] CD46ADC is highly active in an intrafemoral mCRPC xenograft model.

[0681] Because more than 95% of prostate cancers metastasize to bone sites, we further investigated the efficacy of our anti-CD46 ADCs in bone xenograft models. We injected the metastatic castration-resistant prostate cancer (mCRPC) cell line LNCaP C4-2B carrying a firefly luciferase reporter into the femur of NSG mice to create an intraskeletal mCRPC xenograft model. Seven days after transplantation, CD46 ADC (YS5-mcvcpab-MMAF) was injected every 4 days for a total of 4 times. Tumor status was monitored by bioluminescent imaging during and after treatment. Such as Figure 32 As shown in , CD46ADC-treated mice showed profound tumor suppression after the treatment period and continued until the end of the experiment (day 65), indicating that our CD46ADC is highly effective in this endogenous mCRPC xenograft model.

[0682] CD46 is highly expressed in CRPC and mCRPC tissues.

[0683] In addition ...

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Abstract

In various embodiments human anti-CD46 antibodies that are internalizing and enter tumor cells via the macropinocytosis pathway are provided, as well as antibody-drug conjugates (ADCs) developed from these antibodies for diagnostic and / or therapeutic targeting of CD46-overexpressing tumors.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of and priority to USSN 62 / 049,973 filed September 12, 2014, which is hereby incorporated by reference in its entirety for all purposes. [0003] Statement of Rights Concerning Inventions Made Under Federally Sponsored Research and Development [0004] This study was supported in part by grant numbers from The National Institutes of Health: R01CA118919, R01 CA129491, and R01 CA171315. The government has certain rights in this invention. Background technique [0005] Due to their ease of access, tumor cell surface antigens are valuable targets for therapeutic development. The epitope space on the cell surface is highly complex. Associated antigens may include glycosylated proteins and other post-translational modification products not easily predicted from genomic copy number or mRNA expression levels (Liu et al. (2004) Cancer Res. 64:704-710; Kobata and Amano (2005) Immunol. Cel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30A61K47/68A61K39/395A61K38/56A61K31/7036A61K31/5517A61K31/40A61P35/00
CPCC07K16/30A61K51/1027C07K16/3069A61K2039/505C07K2317/30A61K31/7088G01N33/57492G01N2333/70596A61K47/6817C07K16/2896A61K47/6849A61P13/08A61P35/00A61P35/04Y02A50/30C07K2317/21A61K47/6811C07K2317/54C07K2317/569C07K2317/56C07K2317/77C07K2317/55A61K47/6869C07K2317/565
Inventor 刘滨苏扬斯科特·比德林梅尔克里斯托弗·R·贝伦斯李南炅
Owner RGT UNIV OF CALIFORNIA
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