Anti-folate receptor aplha (FRA) antibody-drug conjugates and methods of using thereof

A folic acid receptor and drug technology, applied in drug combination, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, etc.

Inactive Publication Date: 2017-05-10
BIOALLIANCE CV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the increased hydrophobicity of some enzyme-labile linkers can lead to aggregation of ADCs, especially when utilizing strongly hydrophobic drugs

Method used

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  • Anti-folate receptor aplha (FRA) antibody-drug conjugates and methods of using thereof
  • Anti-folate receptor aplha (FRA) antibody-drug conjugates and methods of using thereof
  • Anti-folate receptor aplha (FRA) antibody-drug conjugates and methods of using thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0655] Embodiment 1: the material of embodiment 2-6 and method

[0656] Linker-Drug Synthesis

[0657] The synthesis of compound Tap-18H is shown in the scheme below. The synthesis of intermediate compounds M and O is also shown in the scheme below.

[0658] Synthesis of Compound M

[0659]

[0660] Synthesis of Compound O

[0661]

[0662] Synthesis of compound TAP-18H

[0663]

[0664] See the scheme for the synthesis of compound Tap-18H using PCl 5 or EDCI and NiPr in DMF 2 Et or in CH 2 Cl 2 2-Chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine were used as coupling agents to commercially available 4-nitrophenylglyoxylic acid (glyoxylic acid) is condensed with N-methylpiperazine to give the desired ketoamide. In a typical procedure, N-methylmorpholine (15 mmol) was added to CH with continuous stirring at 0-5 °C 2 Cl 2 (20ml) in a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (5mmol). After 30-40 minutes a white suspension was formed and th...

Embodiment 2

[0723] Example 2: Binding activity of hLK26-based antibody drug conjugates (ADC) in ovarian and lung cancer cells

[0724] hLK26-IgG1-Tap18Hr1 binding activity

[0725] The binding activity of hLK26-IgG1 naked Ab and hLK26-IgG1-Tap18Hr1 was assessed by flow cytometric analysis in FRA-expressing SK-OV-3, OVCAR-3, NCI-h2110 and NCI-h292 cells. Results (Table 8) are shown as the mean fluorescence intensity (MFI) at which optimal binding was achieved with a range of Ab / ADC concentrations. hLK26-IgG1-Tap18Hr1 bound positively to all tested FRA expressing cell lines and exhibited equivalent binding ability to naked Ab hLK26-IgG1. These data demonstrate that conventional ADC hLK26-IgG1-Tap18Hr1 retains the antigenic reactivity of hLK26-IgG1 and binds efficiently to FRA-expressing cancer cells.

[0726] Table 8: Binding of hLK26-IgG1-Tap18Hr1 and unconjugated hLK26-IgG1 to cancer cells

[0727]

[0728] Evaluation of hLK26-Cys variant-Tap18Hr1 location by flow cytometric analy...

Embodiment 3

[0744] Example 3: In vitro cytotoxicity of hLK26-IgG1-Tap18Hr1ADC and hLK26-IgG1 in cell lines expressing FRA

[0745] The in vitro cytotoxic activity of hLK26-IgG1-Tap18Hr1 was evaluated in FRA positive cancer cell lines (SK-OV-3 and OVCAR-3) and FRA negative cell line (Panc 02.03B). Cytotoxicity induced by naked hLK26-IgG1 antibody was also tested in parallel. ADC hLK26-IgG1-Tap18Hr1 induces specific and dose-dependent growth inhibition against FRA-positive cancer cells (SK-OV-3 and OVCAR-3), while it has a lesser growth-inhibitory effect on FRA-negative cells Panc 02.03B , thus demonstrating the antigen specificity of this cytotoxicity (Table 13). Naked Ab hLK26-IgG1 had negligible effect on the viability of treated cells compared to ADC.

[0746] Table 13: In vitro cytotoxic activity of hLK26-IgG1-Tap18Hr1 and hLK26-IgG1

[0747]

[0748] The in vitro cytotoxic activity of site-specifically conjugated hLK26Cys variant-Tap18Hrl was also assessed in SK-OV-3 and OVCAR-3...

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Abstract

The present disclosure provides anti-folate receptor alpha (FRA) antibody-drug conjugates comprising a hydrophilic self-immolative linker. The present disclosures further provide compositions and methods for treating cancers.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 62 / 015,321, filed June 20, 2014, which is hereby incorporated by reference in its entirety. [0003] Submit a sequence listing as an ASCII text file [0004] The entirety of the following, filed as an ASCII text file, is incorporated into this application by reference: Sequence Listing in Computer Readable Format (CRF) (File Name: 606592001040SEQLIST.TXT, Date of Record: June 16, 2015, Size: 44KB). technical field [0005] The present invention is in the field of cancer therapy and provides for the efficacy and specificity of cytotoxic drugs specifically for cancer cells delivered via antibody-drug conjugate (ADC) formats. Background technique [0006] Antibody-drug conjugates (ADCs) are a class of therapeutic agents that combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules. The use of ADCs confers cancer-killin...

Claims

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Application Information

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IPC IPC(8): C07K17/06A61K31/496A61P35/00
CPCC07K2317/73A61K47/6889A61K47/6803C07K16/28A61K31/427C07K2317/24C07K2317/52A61K2039/505A61K47/6849A61P35/00
Inventor 林荣华林士瑶谢昱祁黄久珍李叔桦蔡育英蒋凤琳胡立安
Owner BIOALLIANCE CV
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