Antibody formulation

Details Antibody formulation Antibody formulation

1998-06-12

2001-01-09

Nolan, Patrick (Department: 1644)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

C424S152100, C424S141100, C424S154100, C424S173100, C530S388750

Reexamination Certificate

active

06171586

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to a stable aqueous pharmaceutical formulation comprising an antibody.
BACKGROUND OF THE INVENTION
In the past ten years, advances in biotechnology have made it possible to produce a variety of proteins for pharmaceutical applications using recombinant DNA techniques. Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems. For a protein to remain biologically active, a formulation must preserve intact the conformational integrity of at least a core sequence of the protein's amino acids while at the same time protecting the protein's multple functional groups from degradation. Degradation pathways for proteins can involve chemical instability (i.e. any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (i.e. changes in the higher order structure of the protein). Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example. The three most common protein degradation pathways are protein aggregation, deamidation and oxidation. Cleland et al
Critical Reviews in Therapeutic Drug Carrier Systems
10(4): 307-377 (1993).
Included in the proteins used for pharmaceutical applications are antibodies. An example of an antibody useful for therapy is an antibody which binds to the CD18 antigen. CD18 is the common &bgr; subunit of three heterodimeric membrane integrins restricted to leukocytes that mediate trafficking and adhesion to the vascular endothelium, particularly at sites of inflammation (for reviews see Hynes, R. O.
Cell
, 69:11-25 (1992); Stoolman,
Cell
, 56:907-910 (1989); Jutila et al.
Transplantation
48(5): 727-731 (1989); Springer, T. A.,
Nature
346:425-434 (1990); and Albelda and Buck,
FASEB J.
4:2868-2880 (1990)). The heterodimer containing CD18 and CD11b (also called MAC-1) is found primarily on neutrophils, monocytes, and some lymphocytes whose normal interaction with ICAM-1 on vascular endothelium mediates adhesion and “rolling” of cells along the vasculature. In severe hemorrhagic trauma with concurrent decrease in cardiac output and ischemia, early (within 30 min) neutrophil activation (in response to released cytokines) and up-regulation of MAC-1 increases neutrophil “stickiness”. This precedes extravasation and release of proteases and superoxides that ultimately lead to further tissue damage and increased vascular permeability (Hernandez et al,
Am. J. Physiol
., 253(3 Pt 2): H699-H703 (1987)). Reperfusion following resuscitation exacerbates the edema and necrosis, and leads to multi-organ failure and death. Early treatment with monoclonal antibodies to CD18 in a partally-severed, ischemic rabbit ear trauma model alleviated tissue necrosis following reattachment (Vedder et al.,
J. Clin. Invest
. 81:939-944 (1988)). A humanized antibody showed efficacy in reducing multi-organ damage and death in a rhesus monkey model of decreased cardiac output (created by depletion of ⅔ of blood volume for ~2 hours (Mileski etal.,
Surgery
, 108(2):206-212 (1990)). These studies point to the therapeutic potential of anti-CD18 antibodies for acute treatment of hemorrhagic shock.
Another antigen of interest for targeting with antibodies is the CD20 antigen, also known as “Bp35”. CD20 is a human B cell marker which is expressed during early pre-B cell development and remains until plasma cell differentiation. The CD20 molecule may regulate a step in the activation process which is required for cell cycle initiation and differentiation and is usually expressed at very high levels on neoplastic B cells. Thus, the CD20 surface antigen can be targeted for treating B cell lymphomas. U.S. Pat. No. 5,736,137 issued Apr. 7, 1998 describes the chimeric antibody “C2B8” which binds the CD20 antigen and its use to treat B cell lymphoma.
There is a need in the art for a stable aqueous pharmaceutical formulation comprising an antibody, such as an anti-CD18 or anti-CD20 antibody, which is suitable for therapeutic use.
SUMMARY OF THE INVENTION
Accordingly, the invention provides a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilizabon, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol. Preferably the formulation is stable at a temperature of about 2-8° C. for at least one year, and/or is stable at a temperature of about 30° C. for at least one month and/or is stable following freezing and thawing of the formulation.
The invention also relates to an article of manufacture comprising a container holding a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilizabon, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol.
In yet a further aspect, the invention relates to a method for stabilizing an antibody in an aqueous pharmaceutical formulation by combining a therapeutically effective amount of an antibody not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol.
In a still further aspect, the invention concerns a method of treating a mammal comprising administering a therapeutically effective amount of the aqueous pharmaceutical formulation disclosed herein to a mammal, wherein the mammal has a disorder requiring treatment with the antibody in the formulation. Where the antibody binds CD18, examples of disorders to be treated include hemorrhagic shock, thermal injury (such as that resulting from burns), stroke (including ischemic and hemorrhagic stroke) and myocardial infarction. For an anti-IL8 antibody, disorders to be treated include inflammatory disorders such as adult respiratory distress syndrome (ARDS), hypovolemic shock, ulcerative colitis, and rheumatoid arthritis. Where the antibody binds CD20, disorders to be treated include B cell lymphomas.
These and further aspects of the invention will be apparent to those skilled in the art.


REFERENCES:
patent: 4093606 (1978-06-01), Coval
patent: 4457916 (1984-07-01), Hayashi et al.
patent: 4499073 (1985-02-01), Tenold et al.
patent: 4877608 (1989-10-01), Lee et al.
patent: 4940782 (1990-07-01), Rup et al.
patent: 5032405 (1991-07-01), Huang et al.
patent: 5036049 (1991-07-01), Audhya et al.
patent: 5096885 (1992-03-01), Pearlman et al.
patent: 5147637 (1992-09-01), Wright et al.
patent: 5149653 (1992-09-01), Roser
patent: 5215653 (1993-06-01), Singh et al.
patent: 5262296 (1993-11-01), Ogawa et al.
patent: 5307640 (1994-05-01), Fawzy et al.
patent: 5399670 (1995-03-01), Bhattacharya et al.
patent: 5506342 (1996-04-01), Reno et al.
patent: 5580856 (1996-12-01), Prestrelski et al.
patent: 5589167 (1996-12-01), Cleland et al.
patent: 5608038 (1997-03-01), Eibl et al.
patent: 5654403 (1997-08-01), Smith et al.
patent: 5730980 (1998-03-01), Ulevitch et al.
patent: 5736137 (1998-04-01), Anderson et al.
patent: 5770700 (1998-06-01), Webb et al.
patent: 30771/89 (1989-09-01), None
patent: 2138853 (1995-06-01), None
patent: 303746 (1989-02-01), None
patent: 391444 (1990-10-01), None
patent: 661060 (1995-07-01), None
patent: WO 89/09402 (1989-10-01), None
patent: WO 89/11297 (1989-11-01), None
patent: WO 90/11091 (1990-10-01), None
patent: WO 92/22653 (1992-12-01), None
patent: WO 94/11026 (1994-05-01), None
patent: WO94/26302 (1994-11-01), None
patent: WO 94/26302 (1994-11-01), None
patent: WO 96/41164 (1996-12-01), None
patent: WO 97/04807 (1997-02-01), None
patent: WO97/04807 (1997-02-01), None
patent: WO97/04801 (1997-02-01), None
patent: WO 97/04801 (1997-02-01), None
patent: WO97/17087 (1997-05-01), None
patent: W

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