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Antibodies specific for Trop-2 and their uses

A trop-2, specific technology, applied in the direction of antibodies, specific peptides, anti-tumor drugs, etc., can solve difficult problems

Inactive Publication Date: 2014-09-17
RINAT NEUROSCI CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although various Trop-2 antibody publications have been published (see, e.g., U.S. Patent No. 7,420,041 (antibody AR47A6.4.2), U.S. Patent No. 5,850,854 (antibody BR110), U.S. Patent No. 6,653,104 (antibody RS7), U.S. Patent No. 7,517,964 No. (Antibody RS7), US2012 / 0237518), but it is very difficult to find a monoclonal antibody with high affinity, high specificity and potent cytotoxicity or tumor killing / inhibiting / regression activity

Method used

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  • Antibodies specific for Trop-2 and their uses
  • Antibodies specific for Trop-2 and their uses
  • Antibodies specific for Trop-2 and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Example 1: Detection of Antibody Binding Affinity of Recombinant Anti-Trop-2 Mouse Antibody

[0365] The affinity of the anti-Trop-2 mouse antibody produced by the hybridoma was measured by surface plasmon resonance using a research-grade CM5 sensor chip (Biacore TM AB, Uppsala, Sweden - now GE Healthcare) Biacore TM 2000 or 3000 biosensors. Anti-mouse IgG is the first amine coupled to the surface of the CM5 chip. Multiple anti-Trop-2 mouse antibodies were then captured by anti-mouse IgG. Monomeric Trop-2 ectodomain was prepared by papain digestion of Trop-2-Fc fusion protein, followed by 3-fold serial dilution as the analyte for injection. The affinity of the anti-Trop-2 mouse antibody ranges from 7.5 to 31.8nM. See Table 4.

[0366] Table 4

[0367]

Embodiment 2

[0368] Example 2: Domain mapping of recombinant anti-Trop-2 mouse antibody

[0369] Domain mapping was performed by exchanging the Trop-2 ectodomain with the equivalent region of Trop-1 (EpCAM) or mouse Trop-2. See Figure 4 and 5 . Anti-Trop-2 antibodies 3E9, 6G11, 7E6 and 18B1 (expressed as recombinant mouse IgG2a) do not bind to human Trop-1 or mouse Trop-2, whereas 15E2 binds to mouse Trop-2 but not to human Trop-2 1 combined. These hybrid proteins were expressed as human Fc fusion proteins in 293F cells. Binding of anti-Trop-2 antibodies to these domain hybrids was determined by Biacore. Anti-Trop-2 antibodies are defined to recognize certain human Trop-2 domains when domain swapping results in loss or reduction of binding. Anti-Trop-2 antibodies 3E9, 7E6 and 15E2 bind domains 3 and 4, whereas antibodies 6G11 and 18B1 bind domain 1. See Table 5. Definitions of the different domains of Trop-2 can be found, for example, in Chong et al., J. Biol. Chem. 276(8):5804-13...

Embodiment 3

[0375] Example 3: In vivo curative effect study of Colo205 xenograft model

[0376] In vivo efficacy studies of anti-Trop-2 mouse IgG were performed in a target-expressing colo205 xenograft model. One million colo205 colon cancer cell lines were implanted subcutaneously into 5- to 8-week-old nu / nu mice (day 0). On the next day (Day 1), the mice were randomly assigned to different treatment groups (control IgG, 7E6, 15E2 or 18B1 groups; n=10 / group) according to their body weight. 20 mg / kg of anti-Trop-2 antibody and control mIgG in each treatment group were administered by rapid injection through the tail vein, three times a week for a total of 12 doses. Body weight changes of all experimental animals were monitored daily. Tumor volume was measured twice a week by calipers and calculated using the following formula: tumor volume = (length x width 2 ) / 2. Study when the tumor volume reaches 2000mm 3 terminated before. TGI (percent tumor growth inhibition) was determined by ...

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Abstract

The present invention provides antibodies that specifically bind to trophoblast cell-surface antigen-2 (Trop-2). The invention further provides antibody conjugates comprising such antibodies, antibody encoding nucleic acids, and methods of obtaining such antibodies. The invention further relates to therapeutic methods for use of these antibodies and Trop-2 antibody conjugates for the treatment of a condition associated with Trop-2 expression (e.g., cancer), such as colon, esophageal, gastric, head and neck, lung, ovarian, or pancreatic cancer.

Description

[0001] Related applications [0002] This application claims U.S. Provisional Patent Application No. 61 / 559,015 (filed November 11, 2011), U.S. Provisional Patent Application No. 61 / 640,641 (filed April 30, 2012), and U.S. Provisional Patent Application No. 61 / 717,288 (filed October 23, 2012), which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to antibodies (eg, full-length antibodies or antigen-binding fragments thereof) that specifically bind to a trophoblast cell surface antigen (Trop-2). The present invention further relates to antibody conjugates (such as antibody-drug-conjugates) comprising Trop-2 antibodies, compositions comprising Trop-2 antibodies, and the use of Trop-2 antibodies and conjugates thereof for the treatment of patients with Trop-2 antibodies. 2. A method of expressing a related symptom (such as cancer). Background technique [0004] Trophoblast cell surface antigen (Trop-2), also known a...

Claims

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Application Information

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IPC IPC(8): C07K16/30A61K47/48A61K38/08
CPCA61K47/48569A61K38/08C07K16/30C07K16/28A61K2039/505C07K16/3076A61K47/48561C07K2317/92C07K2317/73A61K47/6817A61K47/6849A61K47/6851A61K47/6859A61K47/6863A61K47/6869A61P35/00A61P35/04C07K16/3015C07K16/3023C07K16/303C07K16/3046C07K16/3069C07K2317/24C07K2317/565C07K2317/732C07K2317/94
Inventor S-H·刘W-H·胡P·施特罗普M·G·多里沃尔斯卡A·拉吉帕尔D·L·谢尔顿T·T·德兰
Owner RINAT NEUROSCI CORP
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