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Humanized Anti-prostate-specific membrane antigen (PSMA) antibody drug conjugates

A prostate-specific, antibody drug technology, applied in a method and composition for the prevention or treatment of PSMA-related diseases or cancer, in the field of inhibition, which can solve problems such as lack of therapeutic index and toxicity

Pending Publication Date: 2020-11-24
AMBRX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ADCs targeting PSMA face challenges due to lack of therapeutic index and toxicity

Method used

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  • Humanized Anti-prostate-specific membrane antigen (PSMA) antibody drug conjugates
  • Humanized Anti-prostate-specific membrane antigen (PSMA) antibody drug conjugates
  • Humanized Anti-prostate-specific membrane antigen (PSMA) antibody drug conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] Example 1: Transient transfection. Approximately 16 hours before transfection, the CHO-S culture was incubated at 0.75x10 6 / mL in FreeStyle CHO medium. The next day, when the cell count reaches 1.4–1.6x10 6 / mL, the cells were transfected. At target cell counts, 400 mM p-acetylphenylalanine (pAF) stock was added to achieve a final culture concentration of 1.4 mM.

[0183] Polyethyleneimine / DNA (PEI / DNA) complexes were prepared as described: DNA (1.42ug / 1x10 6 cells) were dissolved in RPMI medium (5% (v / v) of the total culture volume), the DNA / RPMI mixture was incubated at room temperature for 2 minutes, and the PEI stock (1 mg / mL) was dissolved in a 3:1 ratio ( PEI / DNA (ug / ug)) was added to the DNA solution, and the mixture was incubated at room temperature for 5 minutes.

[0184] The mixture was added gently to the cell culture and vortexed. Transfer the flask to a 32 °C incubator. On day 6 after transfection, western blot analysis was performed. On day 7 afte...

Embodiment 2

[0185] Example 2: Antibody humanization - parental mouse J591 (Liu et al., Cancer Research, 57, 3629-36354, 1997) antibody was humanized by selecting a human framework based on sequence identity to the mouse framework sequence. Light and heavy chain CDRs from mouse antibodies were grafted onto human frameworks separately and analyzed for binding to PSMA antigen. Humanized variants were generated by pairing four human heavy chain frameworks with six light chain frameworks. The variants were transiently expressed in HEK293 cells and supernatants were tested by FACS for binding to PSMA antigen expressed in LnCap cells. Table 4 describes selected heavy chain variable region sequences and 4 light chain variable region sequences used for further studies. Binding assays revealed that four humanized full-length variants, shown as humanized anti-PSMA variants 1, 2, 3 and 4 (Table 4), retained similar binding affinities to the chimeras (Table 4), exhibiting nanovolume Molar concentrat...

Embodiment 3

[0191]Example 3: Recombinant Expression of Anti-PSMA Antibodies - Lead humanized anti-PSMA antibodies were selected and expressed recombinantly in CHO cells by both transient transfection (described in Example 1) and stable mass confluency methods to examine human Expression of the sourced sequence. In the transient transfection and stable mass confluency approaches, proprietary technologies are built into expression vectors and CHO host cells, respectively (see eg WO2018 / 223108). The unnatural amino acid p-acetylphenylalanine (pAF) was incorporated in the PSMA antibody at position A114 (Kabat numbering scheme, (see Kabat et al., NIH Publication No. 369-847, 1993); the position is given in Table 4 by A indicated), said position being the first amino acid residue of the constant region of the heavy chain.

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Abstract

The invention relates to prostate specific membrane antigen humanized antibodies (anti-PSMA) and anti-PSMA antibody drug conjugates. The invention also relates to methods and compositions for using anti-PSMA antibody drug conjugates in inhibiting, preventing or treating PSMA related diseases or cancers.

Description

[0001] References to related applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 650,277, filed March 29, 2018, entitled "Novel Anti-Prostate-Specific Membrane Antigen (PSMA) Antibody Drug Conjugates," the contents of which are incorporated by reference Incorporated into this article as a whole. [0003] sequence listing [0004] This application contains a Sequence Listing which has been filed in ASCII format through the EFS Web and is hereby incorporated by reference herein in its entirety. The ASCII copy was created on March 29, 2019, is named AMBX_0225_00PCT_ST25.txt, and is 37,015 bytes in size. technical field [0005] The present disclosure relates to novel prostate specific membrane antigen (anti-PSMA) antibodies and antibody drug conjugates. More particularly, the present disclosure relates to methods and compositions for inhibiting, preventing or treating PSMA-associated diseases or cancers using anti-PSMA antibody drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K16/30A61K47/68
CPCA61K47/6869A61K38/07A61P13/08A61P35/00C07K16/3069C07K2317/56C07K2317/51C07K2317/515C07K2317/92C07K2317/94C07K2317/24C07K2317/73A61K31/4166A61K45/06A61K47/6889A61K2039/505A61K2039/884A61K47/68031A61K2300/00A61K47/65A61K38/05A61K47/6803A61K39/39558
Inventor S·鲍米克王佳宁夏锦铭W·布拉迪田丰
Owner AMBRX
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