Methods and compositions for promoting immunopotentiation

Abstract

This invention discloses immunopotentiating agents which stimulate an immune resposne. These agents are categorized into single agents that act directly, adjuvants added concurrently with the agents, or heteroconjugates. Heteroconjugate agents eleicit 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.

What is claimed is:  
     
         1 . An immunopotentiating composition comprising: 
 (a) an immunopotentiating protein; and    (b) a second compound having an epitope against which a cellular or humoral immune response is desired.    
     
     
         2 . The composition of  claim 1 , wherein the immunopotentiating protein comprises a protein derived from microorganisms.  
     
     
         3 . The composition of  claim 2 , wherein the protein derived from microorganisms comprises a bacterial protein.  
     
     
         4 . The composition of  claim 3 , wherein the bacterial protein comprises a staphylococcal enterotoxin.  
     
     
         5 . The composition of  claim 1 , wherein the immunopotentiating protein comprises a monoclonal antibody directed against a T cell activation molecule on the cell surface of a T cell.  
     
     
         6 . The composition of  claim 5 , wherein the T cell activation molecule comprises a variable or constant region epitope expressed on an antigen specific T cell receptor polymorphic TcR α, β, γ or δ chain.  
     
     
         7 . The composition of  claim 5 , wherein the monoclonal antibody is directed against non-polymorphic TcR-associated CD3 chains, γ, δ, ε or ζ.  
     
     
         8 . The composition of  claim 7 , wherein the monoclonal antibody comprises OKT3, SP34, or 64.1.  
     
     
         9 . The composition of  claim 5 , wherein the monoclonal antibody is directed against T cell surface antigens distinct from, and not physically associated on the cell surface with, TcR.  
     
     
         10 . The composition of  claim 9 , wherein the monoclonal antibody is directed against Thy-1.  
     
     
         11 . The composition of  claim 9 , wherein the monoclonal antibody is directed against an activation epitope expressed on a member of the Ly-6 protein family.  
     
     
         12 . The composition of  claim 9 , wherein the monoclonal antibody(s) is directed against human CD2.  
     
     
         13 . The composition of  claim 9 , wherein the monoclonal antibody is directed against CD28.  
     
     
         14 . The composition of  claim 1 , wherein the immunopotentiating protein is a bispecific agent, wherein one arm is specific for a T cell activation epitope, and the other arm specific for a T cell subset specific epitope.  
     
     
         15 . The composition of  claim 14 , wherein the bispecific agent comprises a union of two monoclonal antibodies one directed individually against CD3, the other against CD4.  
     
     
         16 . The composition of  claim 1 , wherein the second protein comprises a peptide of from about 8 to about 100 amino acids in length.  
     
     
         17 . The composition of  claim 1 , wherein the second protein comprises a peptide of from about 8 to about 50 amino acids in length.  
     
     
         18 . The composition of  claim 1  wherein the second protein comprises a peptide derived from a tumor-specific or tumor-associated epitope.  
     
     
         19 . The composition of  claim 1 , wherein the second protein comprises a peptide derived from a viral-specific or viral-associated epitope.  
     
     
         20 . The composition of  claim 1 , wherein the second protein comprises a peptide with an amino acid sequence homologous to that derived from a gene in a bacteria, fungus, protozoal or metazoal parasite.  
     
     
         21 . The composition of  claim 19 , wherein the viral-specific or viral-associated epitope comprises an amino acid sequence found on the surface of an HIV virus or which is specific for HIV infected cells.  
     
     
         22 . The composition of  claim 21 , wherein the peptide composition of the viral-specific epitope comprises an epitope from the gp120 envelope protein of HIV-1.  
     
     
         23 . The composition of  claim 22 , wherein the gp120 envelope protein epitope comprises peptides 18, T1, or T2.  
     
     
         24 . The composition of  claim 19 , wherein the viral-specific epitope comprises amino acid sequences homologous with those expressed on the surface of human hepatitis virus.  
     
     
         25 . The composition of  claim 19 , wherein the viral-specific epitope comprises amino acid sequences homologous with those expressed on the cell surface of viruses causing influenza.  
     
     
         26 . The composition of  claim 1 , wherein the immunopotentiating protein and the second protein are conjugated by crosslinking them to each other.  
     
     
         27 . The composition of  claim 1 , wherein the second compound comprises a protein.  
     
     
         28 . The composition of  claim 27 , wherein the protein includes an amino acid sequence against which an immune response is desired.  
     
     
         29 . The composition of  claim 1 , further defined as a heteroconjugate composition wherein the immunopotentiating protein is conjugated with the second compound to form a heteroconjugate agent.  
     
     
         30 . A method of preparing a heteroconjugate agent for eliciting or enhancing a cellular or humoral immune response to an epitope contained within an amino acid sequence, the method comprising the steps of: 
 (a) obtaining an immunopotentiating protein; and    (b) conjugating to said immunopotentiating protein a second compound to form the heteroconjugate agent, the second compound having an epitope against which a cellular or humoral immune response is desired.    
     
     
         31 . A method of eliciting or enhancing a cellular or humoral immune response in a mammal; to an epitope contained within a selected compound, the method comprising preparing an immunopotentiating composition in accordance with  claim 1;  and administering to the mammal an amount of said agent effective to elicit or enhance such a cellular or humoral immune response.  
     
     
         32 . The method of  claim 31 , wherein the mammal is a mouse, hamster, rat, rabbit, farm animal or primate.  
     
     
         33 . The method of  claim 32 , wherein the primate is a human.  
     
     
         34 . A vaccine comprising a immunogenically effective amount of a heteroconjugate agent defined in accordance with  claim 1 , in combination with a pharmaceutically acceptable diluent.  
     
     
         35 . A method of stimulating or enhancing the immune system of a mammal which comprises preparing an immunopotentiating composition which includes an immunopotentiating agent characterized as having an ability to stimulate an immune response; combining the agent in a pharmaceutically acceptable vehicle; administering the resulting compound to the mammal in amounts effective to stimulate an immune response.  
     
     
         36 . The method of  claim 35 , wherein the mammal has tumor.  
     
     
         37 . The method of  claim 35 , wherein the mammal is immuno-compromised.  
     
     
         38 . The method of  claim 35  in which the mammal has an infection.  
     
     
         39 . The method of  claim 36  wherein the immunopotentiating composition further comprises a second compound against which an immune response is desired.  
     
     
         40 . A method of preparing monoclonal antibodies against a selected compound, comprising the steps of: 
 (a) immunizing mammals with an immunopotentiating composition as defined by  claim 1;     (b) fusing lymphoid cells of the immunized mammal with myeloma cells to form fusion products which include hybridomas;    (c) culturing the fusion products in a selective medium to select for said hybridomas;    (d) screening the hybridomas to identify a hybridoma which secretes a monoclonal antibody directed against the selected compound; and    (e) isolating and culturing the identified hybridoma to prepare the monoclonal antibody.    
     
     
         41 . The method of  claim 40  wherein the selected compound is a protein.  
     
     
         42 . The method of  claim 40  wherein the immunopotentiating composition comprises a Staphylococcus enterotoxin.  
     
     
         43 . The method of  claim 40  wherein the immunopotentiating composition comprises an immunopotentiating agent conjugated to the selected compound.  
     
     
         44 . A method for recruiting hematopoietic bone marrow stem cells of an organism, said method comprising administering an immunopotentiating agent in an amount effective to stimulate the development of said stem cells.  
     
     
         45 . The method of  claim 44  wherein the immunopotentiating agent is an anti-CD3 mAb.  
     
     
         46 . The method of  claim 45  wherein the immunopotentiating agent is a Staphylococcus enterotoxin.  
     
     
         47 . A method for enhancing the engraftment of hematopoietic tissue transplants in an individual receiving such a transplant, said method comprising administering to said individual an amount of an immunopotentiating agent effective to stimulate stem cell recruitment.  
     
     
         48 . The method of  claim 47  wherein the immunopotentiating agent comprises an anti-CD3 mAb.  
     
     
         49 . The method of  claim 47  wherein the immunopotentiating agent is a Staphylococcus enterotoxin.  
     
     
         50 . A method of preparing immunological products, comprising the steps of: 
 (a) immunizing mammals with an immunopotentiating composition which includes an immunopotentiating agent; and    (b) obtaining immunological products from said immunized mammal, said products including T cells, B cells or antibodies.    
     
     
         51 . The method of  claim 50 , wherein said immunopotentiating composition further comprises a second compound against which an immune response is desired.  
     
     
         52 . The method of  claim 50 , wherein said immunologic products comprise antibodies, and the method further comprises preparing a gamma globulin fraction from said antibodies.  
     
     
         53 . The method of  claim 50 , wherein said mammal is a human.  
     
     
         54 . A method of adminstering immunologic products to a mammal comprising preparing such products in accordance with  claim 50  and administering said products to a mammal.