Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1995-06-07
2002-06-04
Schwadron, Ronald B. (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C530S387300, C530S388220, C530S388730, C530S388800, C530S388850, C530S867000, C424S143100, C424S144100, C424S155100, C424S153100, C424S156100, C424S172100, C424S174100
Reexamination Certificate
active
06399061
ABSTRACT:
TABLE OF CONTENTS
A. FIELD OF THE INVENTION
B. BACKGROUND OF THE INVENTION
C. SUMMARY OF THE INVENTION
D. BRIEF DESCRIPTION OF THE DRAWINGS
E. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
F. EXAMPLES
I. Radiolabeled Anti-CD20 Antibody 2B8
A. Anti-CD20 Monoclonal Antibody (Murine) Production (“2B8”)
B. Preparation of 2B8-MX-DTPA Conjugate
i. MX-DTPA
ii. Preparation of 2B8
iii. Conjugation of 2B8 with MX-DTPA
iv. Determination of MX-DTPA Incorporation
v. Immunoreactivity of 2B8-MX-DTPA
vi. Preparation of Indium-[111]-labeled 2B8-MX-DTPA (“I2B8”)
vii. Preparation of Yttrium-[90] -labeled 2B8-MX-DTPA (“Y2B8”)
C. Non-Human Animal Studies
i. Distribution of Radiolabeled 2B8-MX-DTPA
ii. Tumor Localization of I2B8
iii. Biodistribution and Tumor Localization Studies with Radiolabeled 2B8-MX-DTPA
D. Human Studies
i. 2B8 and 2B8-MX-DTPA: Immunohistology Studies with Human Tissues
ii. Clinical Analysis of I2B8 (Imaging) and Y2B8 (Therapy)
a. Phase I/II Clinical Trial: Single Dose Therapy Study
b. Phase I/II Clinical Trial: Multiple Dose Therapy Study
II. Chimeric Anti-CD20 Production
A Construction of Chimeric Anti-CD20 Immunoglobulin DNA Expression Vectors
B. Creation of Chimeric Anti-CD20 Producing CHO and SP2/O Transfectomas
C. Determination of Immunological Activity of Chimeric Anti-CD20 Antibodies
i. Human C1q Analysis
ii. Complement Dependent Cell Lyses
iii. Antibody Dependent Cellular Cytotoxicity Effector Assay
III. Depletion of B Cells in vivo Using Chimeric Anti-CD20
A Non-Human Primate Study
B. Clinical Analysis of C2B8
i. Phase I/II Clinical Trial of C2B8: Single Dose Therapy Study
ii. Phase I/II Clinical Trial of C2B8: Multiple Dose Therapy Study
IV. Combination Theraphy: C2B8 and Y2B8
A Preparation of Y2B8
B. Preparation of C2B8
C. Results
V. Alternative Theraphy Strategies
VI. Deposit Information
G. SEQUENCE LISTING
H. CLAIMS
A. FIELD OF THE INVENTION
The references to be discussed throughout this document are set forth merely for the information described therein prior to the filing dates of this document, and nothing herein is to be construed as an admission, either express or implied, that the references are “prior art” or that the inventors are not entitled to antedate such descriptions by virtue of prior inventions or priority based on earlier filed applications.
The present invention is directed to the treatment of B cell lymphoma using chimeric and radiolabeled antibodies to the B cell surface antigen Bp35 (“CD20”).
B. BACKGROUND OF THE INVENTION
The immune system of vertebrates (for example, primates, which include humans, apes, monkeys, etc.) consists of a number of organs and cell types which have evolved to: accurately and specifically recognize foreign microorganisms (“antigen”) which invade the vertebrate-host; specifically bind to such foreign microorganisms; and, eliminate/destroy such foreign microorganisms. Lymphocytes, amongst others, are critical to the immune system. Lymphocytes are produced in the thymus, spleen and bone marrow (adult) and represent about 30% of the total white blood cells present in the circulatory system of humans (adult). There are two major sub-populations of lymphocytes: T cells and B cells. T cells are responsible for cell mediated immunity, while B cells are responsible for antibody production (humoral immunity). However, T cells and B cells can be considered as interdependent—in a typical immune response, T cells are activated when the T cell receptor binds to fragments of an antigen that are bound to major histocompatability complex (“MHC”) glycoproteins on the surface of an antigen presenting cell; such activation causes release of biological mediators (“interleukins”) which, in essence, stimulate B cells to differentiate and produce antibody (“immunoglobulins”) against the antigen.
Each B cell within the host expresses a different antibody on its surface—thus, one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. Accordingly, B cells are quite diverse, and this diversity is critical to the immune system. In humans, each B cell can produce an enormous number of antibody molecules (ie, about 10
7
to 10
8
). Such antibody production most typically ceases (or substantially decreases) when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated; such proliferation can result in a cancer referred to as “B cell lymphoma.”
T cells and B cells both comprise cell surface proteins which can be utilized as “markers” for differentiation and identification. One such human B cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, referred to as “CD20.” CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation. Specifically, 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 (“tumor”) B cells. CD20, by definition, is present on both “normal” B cells as well as “malignant” B cells, ie, those B cells whose unabated proliferation can lead to B cell lymphoma. Thus, the CD20 surface antigen has the potential of serving as a candidate for “targeting” of B cell lymphomas.
In essence, such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are, eg, injected into a patient. These anti-CD20 antibodies specifically bind to the CD20 cell surface antigen of (ostensibly) both normal and malignant B cells; the anti-CD20 antibody bound to the CD20 surface antigen may lead to the destruction and depletion of neoplastic B cells. Additionally, chemical agents or radioactive labels having the potential to destroy the tumor can be conjugated to the anti-CD20 antibody such that the agent is specifically “delivered” to, eg, the neoplastic B cells. Irrespective of the approach, a primary goal is to destroy the tumor: the specific approach can be determined by the particular anti-CD20 antibody which is utilized and, thus, the available approaches to targeting the CD20 antigen can vary considerably.
For example, attempts at such targeting of CD20 surface antigen have been reported. Murine (mouse) monoclonal antibody 1F5 (an anti-CD20 antibody) was reportedly administered by continuous intravenous infusion to B cell lymphoma patients. Extremely high levels (>2 grams) of 1F5 were reportedly required to deplete circulating tumor cells, and the results were described as being “transient.” Press et al., “Monoclonal Antibody 1F5 (Anti-CD20) Serotherapy of Human B-Cell Lymphomas.”
Blood
69/2:584-591 (1987). A potential problem with this approach is that non-human monoclonal antibodies (eg, murine monoclonal antibodies) typically lack human effector functionality, ie, they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fc-receptor mediated phagocytosis. Furthermore, non-human monoclonal antibodies can be recognized by the human host as a foreign protein; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions. For murine-based monoclonal antibodies, this is often referred to as a Human Anti-Mouse Antibody response, or “HAMA” response. Additionally, these “foreign” antibodies can be attacked by the immune system of the host such that they are, in effect, neutralized before they reach their target site.
Lymphocytes and lymphoma cells are inherently sensitive to radiotherapy for several reasons: the local emission of ionizing radiation of radiolabeled antibodies may kill cells with or without the target antigen (eg, CD20) in close proximity to antibody bound to the antigen; penetrating radiation may obviate the problem of limited access to the antibody in bulky or poorly vascularized tumors; and, the total amount of antibody required may be reduced. The radionuclide emits radi
Anderson Darrell R.
Hanna Nabil
Newman Roland A.
Rastetter William H.
Reff Mitchell E.
IDEC Pharmaceutical Corporation
Schwadron Ronald B.
Teskin Robin L.
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