Methods and compositions for promoting immunopotentiation

Abstract

This invention discloses immunopotentiating agents which stimulate an immune response. These agents are categorized into single agents that act directly, adjuvants added concurrently with the agents, or heteroconjugates. Heteroconjugate agents elicit or enhance a cellular or humoral immune response which may be specific for an epitope contained within an amino acid sequence. Enhanced hematopoieses by bone marrow stem cell recruitment was also a result of administering some of these agents. Examples of immunopotentiating agents include monoclonal antibodies and proteins derived from microorganisms (e.g., enterotoxins) which activate T cells. One method of treatment disclosed uses only the immunopotentiating agent to stimulate the immune system. Another uses adjuvants in combination with the agent. A third method employs heteroconjugates. Heteroconjugates comprise: (a) an immunopotentiating protein which is characterized as having an ability to stimulate T cells; and (b) a second protein having an amino acid sequence which includes an epitope against which a cellular or humoral response is desired. This invention also relates to a method of preparing the heteroconjugate, and to a method of stimulating the immune system in vivo in a novel way. One route of stimulation is to activate T cells, in some instances, specific subsets of T cells, by administering heteroconjugates containing an immunopotentiating protein and a second protein, to mammals. For this method of treatment, the second protein in the heteroconjugate is derived from abnormal or diseased tissue, or from an infectious agent; alternatively, the second protein is produced synthetically by standard methods of molecular biology. Sources of the second protein include tumors, viruses, bacteria, fungi, protozoal or metozoal parasites. Monoclonal antibodies or T cells prepared from mammals whose immune systems have responded to administration of the heteroconjugate may be produced and administered to induce passive immunity. A method of preparing a hybridoma which secretes said monoclonal antibodies and use of these monoclonal antibodies and T cells, are also disclosed. This invention is also directed to a vaccine comprising the heteroconjugate.

Description

[0001] The government may own certain rights in the present invention pursuant to NIH grant number 5 RO1-CA-49260.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to immunology, and, more specifically, to the preparation and use of immunopotentiating agents which are capable of eliciting, enhancing and / or otherwise modifying immune responses. These agents, through their ability to elicit or enhance cellular or humoral responses, have potential utility in a variety of disease conditions wherein immunotherapy might be expected to provide a benefit. [0004] 2. Description of Related Art [0005] The body's immune system serves as a defense against a variety of conditions, including, e.g., injury, infection and neoplasia, and is mediated by two separate but interrelated systems, the cellular and humoral immune systems. Generally speaking, the humoral system is mediated by soluble products, termed antibodies or immunoglobulins, which have the abilit...

AI Technical Summary

Benefits of technology

[0033] The term “activation” is generally defined to refer to any change induced in the basal or resting state of T or B cells. This includes, but is not limited to, increased cell proliferation and DNA synthesis, lymphokine and cytotoxic cell production, a rapid rise in intracellular calcium, release of water soluble inositol phosphates, increased IL-2 receptor expression, enhanced proliferative response to IL-2, and enhanced responses to foreign antigens or MHC (23). In contrast, the term “immunopotentiating” is classically defined as the ability to produce an effect on the immune system which enhances the system's ability to respond to foreign antigens. Thus, immunopotentiation may affect the cellular response, humoral response, or both. Exemplary indices of immunopotentiation include, but are not limited to, cell-proliferation, i

Problems solved by technology

One of the major problems in clinical immunology is that the polymorphic antigens of the MHC impose severe restrictions on triggering an immune response.

Another problem is that doses of an invading antigen may be too low to trigger an immune response.

By the time the antigenic level rises, it may be too late for the immune system to save the organism.

The tremendous heterogeneity of the MHC proteins among individuals remains the most serious limiting factor in the clinical application of allograft transplantation.

Attempts to suppress the alloreactivity by drugs or irradiation has resulted in severe side effects that limit their usefulness.

However, the results were often inconsistent due to the inability to standardize individual preparations of antisera.

In addition, the precise nature of the target antigens recognized by the polyclonal reagents could not be defined, thus making scientific analysis difficult.

Although some of these agents, in vitro effects have previously been demonstrated, in vitro activity is often not a reliable predictor of in vivo effects.

One cause of malignant tumor growth is believed to be the inability of the immune system to respond appropriately to tumor antigen.

However, these adjuvants do not selectively act on T cells, or subsets of T cells, and have not been shown capable of overcoming immunodeficiency states.

Unfortunately, current modes of immunotherapy which induce non-specific effector cells are not effective enough in potentiating anti-tumor responses (18).

Immunological responses to HIV infection require the development of both humoral and cell mediated effector mechanisms; however current efforts in treatment and vaccine design have fallen short of success either due to the immunodeficiency associated with the viral infection, or to the low immunogenicity of the vaccine (20).

The development of a safe and effective vaccine against infection with human immunodeficiency virus (HIV) is complicated by a lack of understanding of protective immunity to HIV and disease development, and the absence of an adequate and convenient animal mode

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