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Anti-CD19 antibodies and uses in oncology

A technology of antibodies and human antibodies, applied in the direction of antibodies, chemical instruments and methods, peptides, etc., can solve the problems that cannot be evaluated by efficacy

Inactive Publication Date: 2008-07-09
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, efficacy evaluation of murine anti-CD19 antibodies and anti-CD18 antibody-based immunotoxins in humans produced uncontrolled data that could not be used for efficacy evaluation

Method used

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  • Anti-CD19 antibodies and uses in oncology
  • Anti-CD19 antibodies and uses in oncology

Examples

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Effect test

Embodiment 1

[0460] 6.2 Example 1: Expression of human CD19 in transgenic mice

[0461] The transgenic hCD19TG mice described herein or other transgenic animals expressing human CD19 can be used to evaluate different treatment regimens comprising human, humanized or chimeric anti-CD19 antibodies, e.g. or change over time. Efficacy in human patients with different treatment regimens can be predicted using two indicators, namely: B cell depletion in certain body fluids and / or tissues and monoclonal human or humanized anti-CD19 antibodies Ability to bind to B cells. In particular embodiments, therapeutic regimens that are effective in human CD19 transgenic mice and compositions and methods of the invention can be used to treat B-cell malignancies in humans.

[0462] In order to determine whether human CD19 in transgenic mice (hemizygous TG-1 + / - ) B cells were extracted from the bone marrow, blood, spleen and peritoneal fluid of these mice. Expression of human CD19 and mouse CD19 was asse...

Embodiment 2

[0471] 6.3 Example 2: Anti-CD19 antibody depletion of B cells in vivo

[0472] Mouse anti-CD19 antibody, which binds to human CD19, was evaluated for its in vivo depletion of hCD19TG (TG-1 + / - ) capacity of blood, spleen and lymph node B cells. Each antibody was administered to mice at an amount of 250 or 50 μg / mouse, a single dose approximately 10 to 50 times lower than the dose of 375 mg / m in four doses of anti-CD20 therapy in humans (Maloney et al., J Clin. Oncol, 15:3266-74 (1997) and McLaughlin et al., 12:1763-9 (1998)).

[0473] exist Figure 2A Results are shown in block diagrams of B cells after 7 days of CD19 or paired isotype control (CTL) treatment with HB12a, HB12b or FMC63 anti-CD19 antibody or control. Separate blocks were provided for lymph node, spleen and blood tissues for each anti-CD19 antibody or control. Percentage of channel lymphocyte depletion over 7 days indicated in each block, indicating TG-1 depletion from TG-1 as determined by immunofluorescenc...

Embodiment 3

[0512] 6.4 Example 3: Tissue B cell depletion is FCγR dependent

[0513] The following assay was used to determine whether B cell depletion by anti-CD19 antibodies was dependent on FCγR expression. Mice expressing hCD19 and expressing some FcγRs were generated by cross-breeding hCD19tg with mice lacking expression of some FcγRs. Such mice are used in assays to determine the ability of anti-CD19 antibodies to deplete B cells through pathways involving FcyR expression, eg, ADCC. Accordingly, anti-CD19 antibodies identified in these assays can be used to prepare chimeric, human or humanized anti-CD19 antibodies using the methods described above in Section 5.1. Such antibodies can in turn be used in the compositions and methods of the invention to treat B cell malignancies in humans.

[0514] The innate immune system mediates B cell depletion following anti-CD20 antibody treatment through an FcγR-dependent process. Mouse effector cells express four distinct FcyR types: IgG, hig...

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Abstract

The present invention relates to compositions and methods for the treatment of B-cell diseases and disorders in a subject using therapeutic antibodies that bind to the human CD19 antigen, preferably mediate human antibody-dependent cell-mediated cytotoxicity (ADCC), Said disease + such as, but not limited to, B-cell tumors. The present invention relates to pharmaceutical compositions comprising anti-CD19 antibodies of human or humanized IgG1 and / or IgG3 human isotype. The present invention relates to pharmaceutical compositions comprising human, humanized or chimeric IgG2 and / or IgG4 human isotypes, preferably anti-CD19 antibodies that mediate ADCC in humans. The invention also relates to chimeric anti-CD19 antibodies comprising an IgGl, IgG2, IgG3 or IgG4 isotype that mediates ADCC in humans. In a preferred embodiment, the present invention relates to a pharmaceutical composition comprising a monoclonal human, humanized or chimeric anti-CD19 antibody.

Description

[0001] This invention was made in part under federal government grant numbers CA81776, CA105001, and CA96547 from the National Cancer Institute of the National Institutes of Health, and the National Cancer Institute of the United States of America. This was done with federal government grant number AI56363 from the National Institute of Allergy and Infectious Disease at the Institutes of Health. The US Government has certain rights in this invention. [0002] This application claims U.S. Provisional Patent Application 60 / 653,587 filed February 15, 2005 and filed July 22, 2005 under 35 U.S.C. § 119(e) (35 U.S.C. § 119(e)) Priority to US Provisional Patent Application 60 / 702,063, which is incorporated by reference in its entirety. [0003] 1 Introduction [0004] The present invention relates to methods of treating B cell disorders or diseases, including B cell tumors, in a subject using therapeutic antibodies that bind to the human CD19 antigen. In preferred embodiments, the t...

Claims

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Application Information

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IPC IPC(8): C12P21/08C07K16/00A61K39/395
Inventor T·F·特德Y·哈马古基H·格伦N·雅扎瓦
Owner DUKE UNIV
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