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Anti-cd117 antibodies and uses thereof

An antibody, T114 technology, applied in the direction of antibodies, anti-tumor drugs, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problems of difficult implantation of hematopoietic stem cell transplants

Pending Publication Date: 2022-02-01
美真达治疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although hematopoietic stem cells have considerable therapeutic potential, a limitation hindering their use in the clinic is the difficulty associated with ensuring engraftment of hematopoietic stem cell transplants in the host

Method used

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  • Anti-cd117 antibodies and uses thereof
  • Anti-cd117 antibodies and uses thereof
  • Anti-cd117 antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0632] Preparation of antibody-drug conjugates

[0633] In the ADC of Formula I disclosed herein, the anti-CD117 antibody or antigen-binding fragment thereof is linked to one or more cytotoxic drug moieties (D) (e.g., about 1 to about 20 drug moieties) via a linker L and a chemical moiety Z disclosed herein. / antibody) conjugation. The ADCs of the present disclosure can be prepared by several routes using organic chemistry reactions, conditions and reagents known to those skilled in the art, including: (1) Reactive substituents of antibodies or antigen-binding fragments thereof are reacted with bivalent linker reagents to Form Ab-Z-L as described above, then react with the drug moiety D; or (2) the reactive substituent of the drug moiety is reacted with a divalent linker reagent to form D-L-Z, and then react with the antibody or its Reactive substituents of the antigen-binding fragment react to form an ADC of formula D-L-Z-Ab, such as Am-Z-L-Ab. Additional methods of making ...

Embodiment 1

[0661] Example 1. Identification of Anti-CD117 Antibody 85 (Ab85)

[0662] Anti-CD117 antibody 85 (ie, Ab85) was identified based on the generation of a derivative of the human CK6 antibody (ie, Ab1 ) as described in PCT / US2018 / 057180 (the disclosure of which is incorporated herein by reference in its entirety). Antibody 85 is an antagonistic antibody, which can be determined by assaying the ability of Ab85 to block CD117-mediated activation, as known to those skilled in the art, comprising the amino acid sequence provided below. Briefly, cells that depend on the CD117 ligand SCF1 for proliferation (primary CD34+ cells or Mo7e cells) can be incubated in the presence of CD117-binding antibodies to assess their ability to block the interaction between CD117 and SCF1, This results in a measurable reduction in cell proliferation. Alternatively, simple binding experiments can be performed to measure antagonism of CD117 and SCF1 binding events.

[0663] Antibody HC-85 / LC-85 (Ab85)...

Embodiment 2

[0671] Example 2. Epitope analysis of Ab85

[0672] Chemical cross-linking experiment

[0673] Cross-linking experiments allow direct analysis of non-covalent interactions by high-quality MALDI mass spectrometry. By mixing protein samples containing non-covalent interactions with a specially developed cross-linking mixture (Bich, C et al. Anal. Chem., 2010, 82(1), pp 172–179), it is possible to specifically detection of non-covalent complexes. The resulting covalent binding allows the interacting species to survive the sample preparation process and MALDI ionization. A special high-mass detection system allows the characterization of interactions in the high-mass range.

[0674] Ab85 samples were diluted in distilled water to a concentration of 2.7 mg / mL. 1 μL of diluted Ab85 was then mixed with 1 μL of matrix consisting of recrystallized sinapinic acid matrix (10 mg / mL) in acetonitrile / water (1:1, v / v), TFA (0.1% (K200MALDI Kit). The mixture was crosslinked using CovalX'...

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Abstract

The present disclosure provides compositions and methods useful for the depletion of CD117+ cells and for the treatment of various hematopoietic diseases, metabolic disorders, cancers, e.g., acute myeloid leukemia (AML) and autoimmune diseases, among others. Described herein are antibodies, antigen-binding fragments, and conjugates thereof that can be applied to effect the treatment of these conditions, for instance, by depleting a population of CD117+ cells in a patient, such as a human. The compositions and methods described herein can be used to treat a disorder directly, for instance, by depleting a population of CD117+ cancer cells or autoimmune cells. The compositions and methods described herein can also be used to prepare a patient for hematopoietic stem cell transplant therapy and to improve the engraftment of hematopoietic stem cell transplants by selectively depleting endogenous hematopoietic stem cells prior to the transplant procedure.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application No. 62 / 838,264, filed April 24, 2019, and U.S. Provisional Application No. 62 / 841,733, filed May 1, 2019. The content of each of the foregoing priority applications is incorporated herein by reference. [0003] sequence listing [0004] This application contains a Sequence Listing electronically filed in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on April 20, 2020, named M103034_2150WO_SL.txt, and was 186,529 bytes in size. technical field [0005] The present disclosure relates to anti-CD117 antibodies, antibody drug conjugates (ADCs) and antigen-binding fragments thereof, and the treatment of patients with antibodies or antibody drug conjugates (ADCs) capable of binding to antigens expressed by hematopoietic cells, such as hematopoietic stem cells. There is an approach for patients with various pathologies such as bloo...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K14/435C07K16/28
CPCA61P35/00C12N9/12C12Y207/10001C07K14/70596C07K16/2803C07K2317/34C07K2317/21C07K2317/76
Inventor R.帕尔乔杜里A.博伊塔诺M.库克B.R.皮尔斯
Owner 美真达治疗公司
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