Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing
Reexamination Certificate
1999-03-03
2002-06-18
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
C424S184100, C424S277100, C423S625000, C435S325000, C514S965000, C514S963000
Reexamination Certificate
active
06406689
ABSTRACT:
BACKGROUND OF THE INVENTION
1. The Field of the Invention
The present invention is directed generally to methods and compositions for active specific immunotherapy of tumors. More specifically the present invention is related to methods and compositions for treating tumors with vaccines and with preparations for intratumoral injections and to methods for preparing tumor vaccines and preparations for intratumoral injections that are capable of stimulating immune responses to specific tumor antigens.
2. The Relevant Technology
Basic terminology and general principles in immunology. The foundation of immunology theory rests on the basic idea of self
on-self discrimination, a process that is accomplished by means of recognition mechanisms. Because these recognition mechanisms are used for defeating undesirable microorganisms and for eliminating potentially harmful substances, they are in fact a preeminent part of an individual's defense mechanisms.
Some of these defense mechanisms do not rely on the triggering effect of prior exposure for effecting their protective activity. These are part of the innate or natural immune mechanisms that include physical barriers like the skin, and certain substances, cells and enzymes that are active before exposure to foreign agents. In contrast, the defense mechanisms collectively known as acquired or adaptive immunity can recognize foreign structures and subsequent exposure to such foreign structures leads to a more efficient and effective immune response. See, for example, Donald M. Weir, and John Stewart,
Immunology
, chapter 1, 8th ed., Churchill Livingstone, New York, 1997. (This book will hereinafter be referred to as “
Immunology
”).
A molecule that elicits a specific immune response when introduced into the host tissues is an antigen. Note that the definition of an antigen is arbitrary because specific responsiveness is a property of the host tissues, not of the injected substance. A response to stimulation by antigen is the production of an antibody, a protein that is capable of specific combination with antigen. See, for example,
Immunology
, chapter 3
; The Dictionary of Immunology
, edited by W. John Herbert, Peter C. Wilkinson, and David I. Scott, page 10, Academic Press, London, 1995. (This book will hereinafter be referred to as “
Dictionary of Immunology
”). The response of the host to an antigen on the first encounter is termed the primary immune response.
Dictionary of Immunology
, at p. 132.
The self
on-self discrimination idea in immunology should not be confused with the external/internal dichotomy. It is worth emphasizing in this respect that the physiological reaction that develops through an antibody response is triggered by a foreign agent, whether this agent is harmful or not. In addition, the foreign agent does not necessarily have to be external, for immune responses can also be generated against internal antigens. Sources of such internal antigens include antigens released from disintegrating tissues and antigens that are produced during replicative cycles. Immunity is achieved when the necessary antigen is present and induced antibodies can neutralize the foreign agent. See, for example,
Immunology
at pp. 86-87. Humoral immunity depends on the appearance in the blood of proteins such as those known as antibodies.
For self-non-self discrimination, especially in the context of tumor immunology, cellular immunity is much more important than antibodies. Cellular immunity, also known as cellular cytotoxic immunity or cell-mediated immunity, was originally used to describe localized reactions to organisms mediated by a type of lymphocytes, the T-lymphocytes, and by phagocytes rather than by antibody. It is currently used to describe any response in which antibody plays a subordinate role. It is acknowledged that cell-mediated immunity depends mainly on the development of T-cells that are specifically responsive to the inducing agent, and furthermore cell-mediated immunity is generally active against intracellular organisms. See,
Immunology
, pp. 86-87.
Adjuvants. The natural ability of an antigen to induce an immune response can be modified, and in particular enhanced, by altering or by mixing it with another substance. The procedure or the substance used to enhance immune responses is called an adjuvant. At least three classes of adjuvants have been used for a long time; these are mineral oil emulsions, aluminum compounds, and surface active materials such as saponin, lysolecithin, retinal, Quil A®, some liposomes, and pluronic polymer formulations. See, for example,
Fundamental Immunology
, edited by William E. Paul, at p. 1008, Raven Press, New York (this book will hereinafter be referred to as “
Fundamental Immunology
”). Aluminum adjuvants used alone or in combination include aluminum hydroxide gel, aluminum phosphate, aluminum sulphate, and alums comprising ammonium alum (such as (NH
4
)
2
SO
4
.Al
2
(SO
4
)
3
) and potassium alum. Aluminum hydroxide (hereinafter “AL”) is one of the older adjuvants and it is considered so safe that it has been applied in bacterial and viral vaccines administered to billions of people around the world. Calcium phosphate gel (hereinafter “CP”) has similar properties and is also used in vaccines. Both substances are available in pharmaceutical qualities in most countries worldwide. Techniques for preparing adjuvant-antigen preparations for injection are well known in the art. See, for example, Terry M. Phillips,
Analytical Techniques in Immunochemistry
, pp. 307-10, Marcel Dekker, New York, 1992.
Other adjuvants include complete Freund's adjuvant (a water-in-oil emulsion in which killed, dried, mycobacteria—usually M tuberculosis—are suspended in the oil phase); incomplete Freund's adjuvant (analogous to the complete Freund's adjuvant with no mycobacteria); ISCOM (or immune stimulating complex, comprising lipophilic particles formed by the spontaneous association of cholesterol, phospholipid and the saponin Quil A®); lipopolysaccharide (complex molecules consisting of a lipid core—lipid A—with a polysaccharide side chain that are components of certain bacilli, Lipid A is incorporated into the outer membrane of the bacterium and the polysaccharide projects extracellularly. Their adjuvant potency is associated with lipid A; they are also mitogenic for murine B lymphocytes); and mycobacterial adjuvants (whole, heat killed, dried, mycobacteria—such as
M. tuberculosis, M. avium, M. phlei
, and
M. smegmatis
) that, when suspended in mineral oil and emulsifier, have adjuvant activity with respect to any antigen given with them. Extracts of some mycobacteria, e.g., mycobacterial peptidoglycolipids have similar adjuvant activities. See, for example,
Dictionary of Immunology
at pp. 3, 7, 46, 94, 97, 105, and 116; R. B. Luftig,
Microbiology and Immunology
, pp. 228-29, Lippincott-Raven Publishers, Philadelphia 1998. Microbial adjuvants include
Corynebacterium parvum
and
Bordetella pertussis
. See, for example,
Handbook of Immunology
at 115-16. Use of controlled-release preparations and materials with adjuvant activity and possible sites of action have been described in
Fundamental Immunology
at pp. 1007-09.
Mineral carriers such as aluminum hydroxide, potassium ammonium sulphate, and potassium aluminum sulphate adsorb the antigen on their surface. These common adjuvants have been used at a 0.1% concentration with up to 1 mg protein antigen in 1 ml administered to animals at doses of 0.2-0.5 ml/(kg body weight). See Miroslav Ferencik,
Handbook of Immunochemistry
, p. 115, Chapman & Hall 1993 (this book will hereinafter be referred to as “Handbook of Immunochemistry”). Although Freund's adjuvant is toxic and not used for immunization of human beings, mineral adjuvants such as aluminum hydroxide are common in human medicine. Id. at 116. In addition to alum, other adjuvants in the group of inert carriers include bentonite, latex, and acrylic particles. See
Fundamental Immunology
at 1008.
Combinations of adjuvants can also have adjuvant properties. Fo
Falkenberg Frank W.
Krup Oliver C.
Bansal Geetha P.
Falkenberg Frank W.
Workman & Nydegger & Seeley
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