Anti-cd19 antibodies and uses in b cell disorders

Abstract

The invention relates to immunotherapeutic compositions and methods for the treatment of B cell diseases and disorders in human subjects, such as, but not limited to, B cell malignancies and autoimmune diseases and disorders, using therapeutic antibodies that bind to the human CD19 antigen and that preferably mediate human ADCC. The present invention relates to pharmaceutical compositions comprising human or humanized anti-CD19 antibodies of the IgG1 or IgG3 human isotype. The present invention relates to pharmaceutical compositions comprising human or humanized anti-CD19 antibodies of the IgG2 or IgG4 human isotype that preferably mediate human ADCC. The present invention also relates to pharmaceutical compositions comprising chimerized anti-CD19 antibodies of the IgG1, IgG2, IgG3, or IgG4 isotype that mediate human ADCC. In preferred embodiments, the present invention relates to pharmaceutical compositions comprising monoclonal human, humanized, or chimeric anti-CD19 antibodies.

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 12 / 401,310 (filed Mar. 10, 2009), U.S. patent application Ser. No. 12 / 325,426 (filed Dec. 1, 2008), and U.S. patent application Ser. No. 12 / 275,545 (filed Nov. 21, 2008). U.S. patent application Ser. No. 12 / 401,310 is a continuation of U.S. patent application Ser. No. 11 / 355,905 (filed Feb. 15, 2006), which claims the benefit of U.S. Provisional Application Nos. 60 / 653,587 (filed Feb. 15, 2005) and U.S. 60 / 702,063 (filed on Jul. 22, 2005). U.S. patent application Ser. No. 12 / 325,426 is a continuation of U.S. patent application Ser. No. 11 / 429,545 (filed May 5, 2006), which claims the benefit of U.S. Provisional Application No. 60 / 679,095 (filed May 5, 2005). U.S. patent application Ser. No. 12 / 275,545 is a continuation of U.S. patent application Ser. No. 11 / 450,931 (filed Jun. 8, 2006), which claims the benefit of U.S. Provisional Application Nos. 60 / 689,033 (filed Jun. 8, 2005) ...

AI Technical Summary

Benefits of technology

[0039]In a preferred embodiment of the methods provided by the invention, the anti-CD19 antibody is administered in an amount effective to reduce or deplete circulating B cells, to reduce or deplete circulating immunoglobulin (Ig), or to reduce or deplete both circulating B cells and circulating Ig in a transplant recipient. In one embodiment, the anti-CD19 antibody is administered in an amount effective to reduce or deplete B cells, to reduce or deplete immunoglobulin (Ig), or to reduce or deplete both B cells and Ig in a graft prior to transplantation of the graft to a recipient. In one embodiment, the methods provided by the invention achieve at least a 50% or at least a 75% depletion in circulating B cells. In related embodiments, the depletion in circulating B cells is observed for a period of at least 7 days, at least 30 days, or at least 6 months. In another preferred embodiment, the methods of the invention are effective to reduce panel reactive alloantibodies in the transplant recipient by at least 50%, at least 70%, at least 80%, at least 90%, or at least 95%.

Problems solved by technology

Moreover, the expression of CD20 is not predictive of response to anti-CD20 therapy as only half of non-Hodgkin's lymphoma patients respond to CD20-directed immunotherapy.

However, the perceived unavailability as a target due to cellular internalization, was thought to have presented obstacles to the development of therapeutic protocols that could be successfully used in human subjects.

No conclusions regarding therapeutic efficacy could be drawn from this small group of refractory patients.

Although the xenotransplantation animal models were recognized to be poor prognostic indicators for efficacy in human subjects, the negative results achieved in these animal studies discouraged interest in therapy with naked anti-CD19 antibodies.

These trials generally demonstrated the safety of administering the B4-ricin conjugate to humans; however, results were mixed and response rates were discouraging in comparison to clinical trials with RITUXAN™ (Grossbard et al., Clinical Cancer Research, 5:2392-2398 (1999)).

Thus, the therapeutic evaluation of murine anti-CD19 antibodies and anti-CD19 antibody-based immunotoxins in humans, generated anecdotal data that could not be evaluated for efficacy.

Due to the relatively recent appreciation of the role of humoral immunity in acute and chronic graft rejection, current therapeutic agents and strategies for targeting humoral immunity are less well developed than those for targeting cellular immunity.

The importance of humoral immunity in graft rejection was initially thought to be limited to hyperacute rejection, in which the graft recipient possesses anti-donor HLA antibodies prior to transplantation, resulting in rapid destruction of the graft in the absence of an effective therapeutic regimen of antibody suppression.

Anti-CD19 antibodies may offer advantages over anti-CD20 antibodies in being able to target a wider repertoire of B cells, but their use in transplantation immunotherapy has been limited primarily to the identification and monitoring of B cells.

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