Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof

A technology that binds molecules, tumor antigens, and is used in the treatment of cancer and other diseases and conditions, and can solve problems such as obstacles

Pending Publication Date: 2019-10-11
MACROGENICS INC
View PDF238 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the adaptive immune system can be an effective defense system against cancer and disease, it is often hampered by immune suppression / evasion mechanisms in the tumor microenvironment mediated by reduced / absent costimulatory activity of CD137

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof
  • Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof
  • Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1229] Humanization of HER2 MAB-1

[1230] PCT Publication WO 2001 / 036005 discloses an anti-HER2 / neu antibody, designated "8H11" therein, however, the sequences of the VL and VH domains provided therein are inaccurate. The 8H11 antibody binds to a HER2 / neu epitope that is different from that bound by trastuzumab, margotuximab, and pertuzumab.

[1231] Deriving the correct sequences of the VH and VL domains of the anti-HER2 / neu antibody 8H11 (thus providing HER2-MAB-1 VH (SEQ ID NO:60) and HER2-MAB-1 VL (SEQ ID NO:61)), And multiple rounds of humanization were performed to obtain the above-mentioned humanized VH domain "hHER2 MAB-1 VH1" (SEQ ID NO:64) and humanized VL domain "hHER2 MAB-1VL1" (SEQ ID NO:67 ). During this effort, several potential sequence liabilities were identified in the hHER2 MAB-1 VH1 and hHER2 MAB-1 VL1 domains, and substitutions were made that removed these liabilities while maintaining binding affinity. especially:

[1232] (1) The aspartic acid isome...

Embodiment 2

[1241] Isolation and Characterization of Mouse Anti-CD137 mAb

[1242]A panel of murine monoclonal antibodies specific for human CD137 was screened for antibodies exhibiting high affinity binding. Three antibodies were selected for further study. For this assessment, purified pan T-cells (see above) were stimulated for 72 hours with anti-CD3 / CD28 beads (cell:bead = 1:1) in the presence of IL-2 (100 U / mL). 100 μL of activated T cells (1.0x10 6 cells / mL) and 100 μL of serially diluted (5-fold or 10-fold dilution) test article (antibody or bispecific diabody) were added to each well of a microtiter assay plate, mixed and incubated at room temperature for 45 minutes. Cells were washed with FACS Buffer and then secondary antibody (anti-human-Fc region-APC) was added to each well; mixed and incubated at room temperature for 30 minutes. Cells were then washed with FACS Buffer and then T cell surface marker antibodies (V510-labeled anti-CD4, and FITC-labeled anti-CD8) were added to...

Embodiment 3

[1256] Humanization of mouse anti-CD137 mAb

[1257] Antibodies CD137 MAB-3 and CD137 MAB-4 were selected for humanization. Four rounds of humanization were performed on CD137 MAB-3, which resulted in one humanized VH domain, designated "hCD137 MAB-3 VH1" (SEQ ID NO:76), and three humanized VL domains, designated "hCD137 MAB-3 VL1" (SEQ ID NO:87), "hCD137 MAB-3 VL2" (SEQ ID NO:88), and "hCD137 MAB-3 VL3" (SEQ ID NO:89).

[1258] Three rounds of humanization were performed on CD137 MAB-4, which resulted in one humanized VH domain, designated "hCD137MAB-4 VH1" (SEQ ID NO:92), and two humanized VL domains, designated " hCD137 MAB-4 VL1" (SEQ ID NO:94) and "hCD137 MAB-4 VL2" (SEQ ID NO:95).

[1259] Humanized heavy and light chain variable domains with a particular anti-CD137 antibody (eg, CD137 MAB-3) can be used in any combination and specific references to humanized chains are made by reference to specific VH / VL domains. A combination, eg, a humanized antibody comprising hCD...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention is directed to binding molecules that possess one or more epitope-binding sites specific for an epitope of CD137 and one or more epitope-binding sites specific for an epitope ofa tumor antigen ("TA") (e.g., a "CD137 x TA Binding Molecule"). In one embodiment, such CD137 x TA Binding Molecules will be bispecific molecules, especially bispecific tetravalent diabodies. Alternatively, such CD137 x TA Binding molecules will be bispecific trivalent binding molecules. The CD137 x TA Binding Molecules of the invention are capable of simultaneous binding to CD137, and a TA. The invention is directed to pharmaceutical compositions comprising the CD137 x TA Binding Molecules, methods of using the same to treat cancer and other disease and conditions. The invention also providesnovel CD137-binding molecules, and HER2 / neu-binding molecules, as well as derivatives thereof and uses thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Patent Application Serial Nos. 62 / 463,353 (filed February 24, 2017; pending) and 62 / 597,594 (filed December 12, 2017; pending), both applications Incorporated herein by reference in its entirety. [0003] Reference to Sequence Listing [0004] Pursuant to 37 C.F.R.1.821 and the following clauses, this application includes one or more Sequence Listings on a computer-readable medium (file name: 1301_0149PCT_ST25.txt, created on February 11, 2018, and has a size of 309,094 bytes ), which is incorporated herein by reference in its entirety. technical field [0005] The present invention relates to binding molecules having one or more epitope binding sites specific for an epitope of CD137 and one or more epitope binding sites specific for an epitope of a tumor antigen ("TA") (e.g. "CD137x TA binding molecule"). In one embodiment, such CD137x TA binding molecule will be a bispecific...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): A61K39/395A61P35/00
CPCG11C13/0004G11C15/04A61P35/00C07K16/2866C07K16/2878C07K16/32A61K2039/507C07K2317/24C07K2317/31C07K2317/33C07K2317/35C07K2317/565C07K2317/75C07K2317/76C07K2317/92C07K2317/94G11C13/0026G11C13/004G11C15/046G11C2013/0045C07K2317/626A61K39/3955C07K2317/73A61K39/39558A61K2039/505A61K45/06G11C15/00
Inventor 刘丽勤C·K·兰姆G·迪德里奇莱斯利·S·约翰逊保罗·A·摩尔埃兹奥·泊韦尼
Owner MACROGENICS INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com