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Cd8a-binding fibronectin type iii domains

A technology of structural domains and proteins, applied in the direction of recombinant DNA technology, animal/human proteins, hybrid peptides, etc., can solve the problems of changes in the number and location of immune cells, and the inability to reflect dynamic and spatial information

Active Publication Date: 2019-09-10
JANSSEN BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current methods of monitoring lymphocytes from whole blood or biopsies from heterogeneous tumors do not reflect the dynamic and spatial information that may be required to monitor immune responses to therapeutic interventions, many of which elicit systemic changes in immune cell numbers and localization

Method used

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  • Cd8a-binding fibronectin type iii domains
  • Cd8a-binding fibronectin type iii domains
  • Cd8a-binding fibronectin type iii domains

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0119] The present invention also provides the following non-limiting embodiments.

[0120] 1) An isolated FN3 domain that specifically binds to the human CD8A protein comprising the amino acid sequence of SEQ ID NO:35.

[0121] 2) The isolated FN3 domain of embodiment 1, wherein the FN3 domain cross-reacts with the cynomolgus monkey CD8A protein comprising the amino acid sequence of SEQ ID NO:271.

[0122] 3) The isolated FN3 domain according to embodiment 2, wherein

[0123] a) The FN3 domain is based on the Tencon sequence of SEQ ID NO:1;

[0124] b) The FN3 domain is based on the Tencon27 sequence of SEQ ID NO: 4; and / or

[0125] c) The FN3 domain is isolated from a library containing the sequence of SEQ ID NO: 2, 3, 5, 6, 7 or 8.

[0126] 4) The isolated FN3 domain of embodiment 3, wherein the FN3 domain is conjugated to a second molecule.

[0127] 5) The isolated FN3 domain of embodiment 4, wherein the second molecule is a detectable label.

[0128] 6) The isolated FN3 domain of embod...

Embodiment 1

[0149] Example 1. Construction of a TENCON library with randomized loops

[0150] Tencon (SEQ ID NO:1) is an immunoglobulin-like scaffold, fibronectin type III (FN3) domain, which is designed from the consensus sequence of 15 FN3 domains of human tenascin-C (Jacobs et al. , Protein Engineering, Design, and Selection, 25:107-117,2012; U.S. Patent No. 8,278,419). The crystal structure of Tencon shows six surface exposed loops that connect seven β-strands. These loops or selected residues within each loop can be randomized to construct a library of fibronectin type III (FN3) domains that can be used to select novel molecules that bind to specific targets.

[0151] Tencon:

[0152] LPAPKNLVVSEVTEDSLRLSWTAPDAAFDSFLIQYQESEKVG EAINLTVPGSERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAEFT T (SEQ ID NO 1):

[0153] Use tencon scaffolds and various design strategies to generate various libraries. In general, libraries TCL1 and TCL2 produced good conjugates. The production of TCL1 and TCL2 libraries is des...

Embodiment 2

[0206] Example 2: Generation of TENCON library with alternative binding surface

[0207] The choice of residues to be randomized in a particular library design determines the overall shape of the interaction surface generated. X-ray crystallographic analysis of the maltose binding protein (MBP)-binding FN3-domain-containing scaffold protein selected from the library in which the BC, DE and FG loops were randomized showed that it has a largely curved interface suitable for the active site of MBP (Koide et al., Proc Natl Acad Sci USA 104:6632-6637, 2007). In contrast, it was found that the ankyrin repeat scaffold protein selected to bind to MBP has a flatter interaction surface and binds to the outer surface of MBP away from the active site (Binz et al., Nat Biotechnol 22:575-582, 2004 ). These results indicate that the shape of the binding surface of the scaffold molecule (curved versus flat) can determine which target proteins or specific epitopes on those target proteins can b...

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Abstract

Fibronectin type III domains (FN3) that specifically bind to CD8A, related polynucleotides capable of encoding CD8A-specific FN3 domains, cells expressing the FN3 domains, as well as associated vectors, and detectably labeled FN3 domains are useful in therapeutic and diagnostic applications.

Description

[0001] Sequence Listing [0002] This application contains a sequence listing, which has been electronically submitted in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on December 5, 2017 is named JBI5112WOPCT_SL.txt and has a size of 266,978 bytes. Technical field [0003] The present invention relates to a fibronectin type III (FN3) domain that specifically binds to cluster of differentiation 8a (CD8a). Such FN3 domains can be used in, for example, medical imaging, diagnosis, and drug therapy. Methods of producing such molecules and diagnostic agents containing such molecules are also provided. Background technique [0004] In the rapidly developing field of cancer immunotherapy, several new immunotherapies have recently been approved by the FDA, and more therapies are currently in clinical trials for various cancers. In addition, cells, small molecules, antibody-based immunotherapies and their combinations are undergoing rigorous ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K49/00G01N33/53
CPCA61K49/0002A61K51/088G01N33/566G01N33/574G01N33/57492C07K14/78G01N33/56966G01N33/53G01N2333/70517G01N2333/78C12N15/09C07K19/00G01N33/6887G01N33/68G01N33/534G01N33/569A61K49/14
Inventor 丽贝卡·霍金斯史蒂文·雅各布斯曼纽尔·塞普尔韦达
Owner JANSSEN BIOTECH INC
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