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Antibody-drug conjugates comprising Anti-tm4sf1 antibodies and methods of using the same

A technology of conjugates and antibodies, applied in the direction of antibodies, drug delivery, pharmaceutical formulations, etc.

Pending Publication Date: 2021-12-31
安吉克公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although antibody-drug conjugates targeting TM4SF1 have been considered previously, see, e.g., Visintin et al. Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature, Mol Cancer Ther 2015(14)(8) 1868-1876, but in order for anti-TM4SF1 ADCs to fulfill their promise as solid tumor therapies, TM4SF1-targeting ADCs with reduced toxicity to normal vessels, especially arteries, are needed

Method used

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  • Antibody-drug conjugates comprising Anti-tm4sf1 antibodies and methods of using the same
  • Antibody-drug conjugates comprising Anti-tm4sf1 antibodies and methods of using the same
  • Antibody-drug conjugates comprising Anti-tm4sf1 antibodies and methods of using the same

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0388] Example 1: Characterization of Exemplary Anti-TM4SF1 Antibodies

[0389] affinity

[0390] Antigen binding affinities of anti-TM4SF1 antibodies containing various Fc mutations were examined by cell-based flow cytometry assays. Variants of the exemplary anti-TM4SF1 antibody AGX-A07 comprising the Fc region mutation N297C (“C” variants) or a combination of N297C and mutations M252Y, S254T, and T256E (“YTEC” variants), using HUVEC cells (primary umbilical cord Venous vascular endothelial cells; PCS-100-010 TM )taking the test. bound EC 50 The value is displayed in image 3 Middle (upper left panel), where A07-wt corresponds to the AGX-A07 antibody without Fc region mutation. Similarly, in immortalized mouse endothelial MS-1 cells (MILE SVEN 1; CRL-2279 TM ) and the "C" variant of the murine surrogate (referred to as "MS" in the figure) and the "YTEC" variant were tested. bound EC 50 The value is displayed in image 3 Middle (upper and lower right panels), wher...

Embodiment 2

[0401] Example 2: Antibody-Drug Conjugates Containing Exemplary Anti-TM4SF1 Antibodies

[0402] Antibody-drug conjugates (ADCs) containing exemplary anti-TM4SF1 antibodies were prepared and tested in in vitro and in vivo studies. figure 1 with figure 2 Provides the use of maleimide conjugation ( figure 2 ) or bromoacetamide conjugated ( figure 1 ) the structure of the prepared ADC; 1 4 S,1 6 S,3 2 S,3 3 S,2R,4S,10E,12E,14R)-8 6 -Chloro-14-hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinano-3(2,3)-oxirano-8(1,3)-benzocyclotetradecane (Benzenacyclotetradecaphane)-10,12-dien-4-yl N-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)-N-methyl base-L-alanine ester and 1 4 S,1 6 S,3 2 S,3 3 S,2R,4S,10E,12E,14R)-8 6 -chloro-1 4 -Hydroxy-8 5 ,14-Dimethoxy-3 3 ,2,7,10-Tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinano-3(2,3)-oxirano-8(1,3)-benzocyclotetradecane -10,12-dien-4-yl(S)-1-bromo-26,27-dimethyl-2,18,25-trioxo-6,9,12,15-tet...

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Abstract

Antibody-drug conjugates (ADCs) are described, comprising anti-TM4SF1 antibodies, and antigen-binding fragments thereof. Methods of use of said ADCs are also described.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 811,411, filed February 27, 2019, and U.S. Provisional Application No. 62 / 967,377, filed January 29, 2020, each of which is incorporated by reference Incorporated into this article as a whole. Background technique [0003] There remains a need in the art for cancer therapeutics, particularly those with an improved therapeutic spectrum that can regress primary tumors as well as invasive tumor cells and metastases. [0004] Cancer therapies aimed at destroying tumor blood vessels have failed clinical trials in the past due to toxicity. Examples include vascular disrupting agents such as combretastatin (CA4P). See, eg, Grisham et al. Clinical trial experience with CA4P anticancer therapy: focus on efficacy, cardiovascular adverse events, and hypertension management. Gynecol Oncol Res Pract. 2018; 5:1.. In the Phase II FALCON study, CA4P reduced overall survival From 16.2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/10A61K38/05A61K48/00C07K16/28C07K16/32C07K19/00
CPCC07K16/28C07K2317/52C07K2317/71C07K2317/94A61K2039/505A61K47/6849A61K47/6859A61K47/6865A61K47/6851A61K9/0019A61K47/68033C07K2317/21
Inventor 保罗·A·贾米内史守卿爱德华·H·哈伦纳德·G·普雷斯塔马尼什·S·胡德利卡
Owner 安吉克公司
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