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Compositions and methods for the depletion of cd5+ cells

a technology of cd5+ cells and cd5+ cells, which is applied in the field of compositions and methods for the depletion of cd5+ cells, can solve the problems of serious complications, impede the use of hematopoietic engraftment in the clinic, and difficulty in ensuring engraftment of hematopoietic cells, so as to prevent or reduce the likelihood of rejection

Inactive Publication Date: 2020-09-03
MAGENTA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for preventing rejection of hematopoietic stem cells in patients who need a transplant. This is done by administering an antibody or antigen-binding fragment that targets a protein called CD5. The method can be used to treat various disorders such as stem cell disorders, immunodeficiencies, metabolic disorders, and cancers. The antibody or antigen-binding fragment can be administered before or after the transplant to deplete a population of immune cells that may attack the stem cells. Overall, this method helps to prevent rejection and improve the success of hematopoietic stem cell therapy.

Problems solved by technology

While hematopoietic stem cells have significant therapeutic potential, a limitation that has hindered their use in the clinic has been the difficulty associated with ensuring engraftment of hematopoietic stem cell transplants in a host.
Unfortunately, efforts to induce tolerance of the hematopoietic stem cell transplantation in the patient often result in serious complications.

Method used

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  • Compositions and methods for the depletion of cd5+ cells
  • Compositions and methods for the depletion of cd5+ cells
  • Compositions and methods for the depletion of cd5+ cells

Examples

Experimental program
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Effect test

example 1

Binding Analysis of Anti-CD5 Antibodies

[0701]To determine the binding characteristics of anti-CD5 antibody 5D7 hIgG1, antibody binding studies were performed at 25 degrees Celsius in 1×PBS supplemented with 0.1% w / v bovine serum albumin with a Pall ForteBio Octet Red96 using biolayer interferometry (BLI). The purified human anti-CD5 antibody (5D7) was immobilized onto anti-human Fc biosensors (AHC; Pall ForteBio 18-5063) and incubated with 50 nM of purified human CD5 ectodomain). The binding characteristics of anti-CD5 antibody 5D7 are shown in Table 3. Anti-human CD5 antibody 5D7 as used in Examples 1 to 5 is a humanized version of murine antibody 5D7 (see US 2008 / 0254027). The sequences of antibody 5D7 as used herein are described in SEQ ID Nos: 257 and 258 (heavy and light chain variable region amino acid sequences) and SEQ ID Nos: 29 to 34 (heavy and light chain CDRs).

TABLE 3Binding kinetics of 5D7 to human CD5 ectodomainConc.ResponseKD KONKDIS Full Antibody(nM)(nm)(M)(1 / Ms)(1 / s...

example 2

Cell Line Binding Analysis of Anti-CD5 Antibodies

[0702]MOLT-4 cells (i.e., an immortalized human T lymphoblast cell line) were plated at 20,000 cells / well and stained with a titration of the indicated murine anti-CD5 antibodies (i.e., L17F12, UCHT2, 205919, and CRIS-1) for 2 hours at 4° C. Secondary anti-mouse AF488 stain, at a constant amount, was added for 30 minutes at 4° C. After washing, plates were run on a flow cytometer and binding of the indicated antibody (and the negative control, i.e., mIgG1) was determined based on geometric mean fluorescence intensity in the AF488 channel. Results from these assays are provided in FIG. 1.

[0703]As shown in FIG. 1, the murine anti-CD5 antibodies L17F12 (Thermo Fisher), UCHT2 (BioLegend), 205919 (Novus Biologicals), and CRIS-1 (Novus Biologicals) bound to human T lymphoblast cells (i.e. MOLT-4 cells), with an EC50=207 pM (L17), 354 pM (UCH), 1350 pM (205), and 43 pM (CRIS).

example 3

Primary Cell Binding Analysis of Anti-CD5 Antibodies

[0704]Primary human T-cells were plated at 8×104 cells / well and stained with a titration of the human anti-CD5 antibody 5D7 for 2 hours at 37° C. Secondary anti-mouse AF488 stain, at a constant amount, was added for 30 minutes at 4° C. After washing, plates were run on a flow cytometer and binding of the anti-CD5 5D7 antibody (and the negative control, i.e., hIgG1) was determined based on geometric mean fluorescence intensity in the AF488 channel. Results from these assays are provided in FIG. 2.

[0705]As shown in FIG. 2, the anti-CD5 antibody 5D7 bound to primary human T-cells with an EC50=3.0 pM.

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Abstract

The invention provides anti-CD5 antibodies, antigen-binding fragments thereof, and antibody drug conjugates thereof, for use in treating, for example, a stem cell disorder, cancer, or autoimmune disease, among other hematological and proliferative diseases. Compositions and methods for depleting populations of CD5+ cells, such as CD5+ cancer cells and CD5+ immune cells are described, and can be used to treat cancers and autoimmune diseases directly as stand-alone therapies by eradicating cancerous cells and autoreactive immune cells that express CD5 and / or to prepare a patient for hematopoietic stem cell transplantation, for instance, by depleting populations of CD5+ immune cells that cross-react with, and mount an immune response against, non-self hematopoietic stem cells.

Description

RELATED APPLICATIONS[0001]This application is a continuation of International Application No. PCT / US2018 / 063175, filed on Nov. 29, 2018, which claims the benefit of priority to U.S. Provisional Patent Appln. No. 62 / 592,214, filed on Nov. 29, 2017. The contents of the aforementioned applications are incorporated by reference herein in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 15, 2020, is named M103034_1060US_T1_SL.txt and is 71,679 bytes in size.BACKGROUND OF THE INVENTION[0003]Despite advances in the medicinal arts, there remains a demand for treating pathologies of the hematopoietic system, such as diseases of a particular blood cell, metabolic disorders, cancers, and autoimmune conditions, among others. While hematopoietic stem cells have significant therapeutic potential, a limitation that ...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K38/12C07K16/28
CPCA61K2039/505C07K2317/92A61K47/6849A61K47/6803A61K38/12C07K16/2896A61P35/00A61K47/6831A61K47/6817A61K31/5365A61K38/05A61K31/704A61K31/5517A61P7/06A61P37/00A61P31/18A61P3/00
Inventor BOITANO, ANTHONYCOOKE, MICHAELPALCHAUDHURI, RAHULMCDONOUGH, SEAN
Owner MAGENTA THERAPEUTICS INC
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