Fordham University

University of Connecticut

Mount Sinai School of Medicine

University of Notre Dame Du Lac

Pramod K Srivastava

Rajiv Y Chandawarkar

Robert J Binder

Brian M Baker

Zihai Li

Ion Mandoiu

Nathalie E Blachere

Fei Duan

Cory A Brennick

Mariam M George

Marmar Moussa

Robert Binder

Described herein are methods of identifying immunologically protective neo-epitopes from the cancer tissue DNA of cancer patients using biophysical principles as well as bioinformatics techniques. The identification of immunologically protective neo-epitopes provides pharmaceutical compositions with a limited number of tumor-specific peptides suitable for personalized genomics-driven immunotherapy of human cancer. Specifically disclosed herein is a method of using the conformational stability of an epitope in an MHC protein-binding groove to predict immunogenicity of peptides in a putative neo-peptide set from a tumor from a cancer patient. Pharmaceutical compositions and methods of administration are also included.

Identification of immunologically protective neo-epitopes for the treatment of cancers

Described herein is an unbiased method of identifying tumor rejection mediating neoepitopes (TRMNs). Putative neoepitopes from a cancer cell exome sequence from a cancer patient are putative neoepitopes are unbiased by MHC binding and/or CD8T* reactivity. By plotting the putative neoepitope ICs on one axis, and the non-mutated amino acid sequence ICs on a perpendicular axis to provide a bivariate scatter plot, novel TRMNs are identified TRMNs the neoepitopes in the bivariate scatter plot which are in the space greater than 501 nM on the x-axis and greater than 501 nM on the y-axis. Peptides and nucleic acids for expressing peptides including the TRMNs are also described.

Unbiased identification of tumor rejection mediating neoepitopes

Described herein are methods of identifying tumor-specific epitopes from the cancer tissue DNA of cancer patients using both DNA sequencing and bioinformatics techniques. The identification of tumor-specific epitopes provides pharmaceutical compositions with a limited number of tumor-specific peptides suitable for personalized genomics-driven immunotherapy of human cancer. Specifically disclosed herein is a novel index called the Differential Agretopic Index (DAI) for the epitope which allows prediction of whether immunization with a particular epitope will be protective against the tumor. Pharmaceutical compositions and methods of administration are also included.

Identification of tumor-protective epitopes for the treatment of cancers

The present invention relates to the use of alpha (2) macroglobulin complexes isolated from the serum of a mammal. The invention also relates to methods for making such complexes and compositions comprising alpha (2) macroglobulin complexes, isolated from the serum of a mammal, wherein such compositions are used in methods for the treatment and prevention of cancer and infectious disease. The invention also relates to methods for treating and preventing cancer and infectious disease using such complexes comprising, isolated from the serum of a mammal. The invention also encompasses methods for production of alpha (2) macroglobulin complexes.

Methods and compositions for the treatment of cancer and infectious disease using alpha(2) macroglobulin-antigenic molecule complexes

The present invention relates to methods of improving a treatment outcome comprising administering a heat shock protein (HSP) preparation or an &#x3b1;-2-macroglobulin (&#x3b1;2M) preparation with a non-vaccine treatment modality. In particular, an HSP preparation or an &#x3b1;2M preparation is administered in conjunction with a non-vaccine treatment modality for the treatment of cancer or infectious diseases. In the practice of the invention, a preparation comprising HSPs such as but not limited to, hsp70, hsp90 and gp96 alone or in combination with each other, noncovalently or covalently bound to antigenic molecules or &#x3b1;2M, noncovalently or covalently bound to antigenic molecules is administered in conjunction with a non-vaccine treatment modality.

Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality

Methods and compositions for the treatment of cancer and infectious disease using alpha (2) macroglobulin-antigenic molecule complexes

The present invention relates to methods and compositions for the prevention and treatment of infectious diseases, and cancers. The methods of the invention comprises complexing a population of antigenic proteins or antigenic peptides derived from antigenic cells or viral particles to one or more different heat shock proteins in vitro. The population or the protein preparation used to produce the antigenic peptides comprises at least 50% of the different proteins or at least 50 different proteins of the antigenic cells or viral particles. Methods for making antigenic peptides comprise digesting a protein preparation of antigenic cells, a cellular fraction thereof, or of viral particles with one or more proteases, or exposing the protein preparation to ATP, guanidium hydrochloride, and/or acidic conditions.

Methods for preparing compositions comprising heat shock proteins useful for the treatment of cancer and infectious disease

The present invention relates to methods and compositions for eliciting an immune response and the prevention and treatment of primary and metastatic neoplastic diseases and infectious diseases. The methods of the invention comprise administering a composition comprising an effective amount of a complex, in which the complex consists essentially of a heat shock protein (hsp) noncovalently bound to an antigenic molecule. 'Antigenic molecule' as used herein refers to the peptides with which the hsps are endogenously associated in vivo as well as exogenous antigens/immunogens (i.e., with which the hsps are not complexed in vivo) or antigenic/immunogenic fragments and derivatives thereof. In a preferred embodiment, the complex is autologous to the individual. The effective amounts of the complex are in the range of 10-600 micrograms for complexes comprising hsp70, 50-1000 micrograms for hsp90, and 10-600 micrograms for gp96. The invention also provides a method for measuring tumor rejection in vivo in an individual, preferably a human, comprising measuring the generation by the individual of MHC Class I-restricted CD8+ cytotoxic T lymphocytes specific to the tumor. Methods of purifying hsp70-peptide complexes are also provided.

Compositions and methods for the prevention and treatment of primary and metastatic neoplastic diseases and infectious diseases with heat shock/stress proteins

The present invention relates to complexes of alpha (2) macroglobulin associated with antigenic molecules for use in immunotherapy. The invention relates to methods for using such compositions in the diagnosis and treatment of immune disorders, proliferative disorders, and infectious diseases.

Complexes of alpha (2) macroglobulin and antigenic molecules for immunotherapy

The present invention relates to the use of alpha (2) macroglobulin ('&#x3b1;2M') receptor as a heat shock protein receptor, cells that express the &#x3b1;2M receptor bound to an HSP, and antibodies and other molecules that bind the &#x3b1;2M receptor-HSP complex. The invention also relates to screening assays to identify compounds that modulate the interaction of an HSP with the &#x3b1;2M receptor, and methods for using compositions comprising &#x3b1;2M-receptor sequences for the diagnosis and treatment of immune disorders, proliferative disorders, and infectious diseases.

Alpha(2) macroglobulin receptor as a heat shock protein receptor and uses thereof

The present invention relates to the use of alpha (2) macroglobulin ('&#x3b1;2M') receptor as a heat shock protein receptor, cells that express the &#x3b1;2M receptor bound to an HSP, and antibodies and other molecules that bind the &#x3b1;2M receptor-HSP complex. The invention also relates to screening assays to identify compounds that interact with the &#x3b1;2M receptor, and modulate the interaction of the &#x3b1;2M receptor with its ligand, such as HSPs, and methods for using compositions comprising &#x3b1;2M-receptor sequences for the diagnosis and treatment of immune disorders, proliferative disorders, and infectious diseases.

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Avon, CT, United States of America

Pramod K Srivastava