The Rockefeller University

The University of Texas System

The Scripps Research Institute

Other

The Scripps Institute

Bruce A Beutler

Anthony Cerami

Stephen D Wolpe

Dale L Boger

Alexander N Poltorak

David F Crawford

Pingping Wang

Xue Zhong

Karsten Peppel

Evan Nair-Gill

Flavia M Bazzoni

Jinglei Zhang

Koichi Tabeta

Ying Wang

The present disclosure generally relates to compositions and methods for cancer immunotherapy, as well as hematopoietic recovery following cancer treatment such as chemotherapy or irradiation.

Compositions and methods for cancer therapy

A diprovocim compound that corresponds in structure to structural Formula V is disclosed, wherein A, W, Z, R, R, Rand R(when present) are defined within. A diprovocim compound has immune-adjuvant properties on human and mouse cells in culture and on in vivo immunization of mice. A composition containing a diprovocim and a method of using a compound are also disclosed. The immunostimulatory activity of a diprovocim compound is similar to that of LPS, to which there is no apparent structural similarity. A contemplated compound bears no structural similarity to either the TLR1/TLR2 lipoprotein agonists nor to any other synthetic TLR agonist, and is remarkably easy to prepare and synthetically modify. 

Diprovocims: a new and potent class of TLR agonists

A TLR-independent adjuvant compound that corresponds in structure to Formula I, below, or its pharmaceutically acceptable salt is disclosed in which X, Y, Z, n, R, R, R, Rand W are defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.

TLR-independent small molecule adjuvants

A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same. 

Neoseptins: small molecule adjuvants

Compositions and methods are provided for treatment of autoimmune and other related diseases. 3d, a point mutation of the protein uncoordinated-93b (unc-93B), unc-93A, unc-93B, and unc-93C, polypeptides, nucleic acids encoding them and methods for making and using them, for example, to produce transgenic non-human animals.

Compositions and methods for treatment of autoimmune and related diseases

The present invention describes a mutant TLR-4 in mice that does not recognize endotoxin and therefore does not stimulate the secretion of TNF from macrophages. Methods of detecting the mutation are provided; as are methods screening for drugs that may stimulate TNF production. Finally methods of incorporating and expressing the mutant TLR-4 genes into a host cell are contemplated.

LPS-response gene compositions and methods

An inflammatory cytokine is disclosed which has been isolated from cells that have been incubated with a stimulator material. The inflammatory cytokine comprises a protein that is capable of binding to heparin, inducing localized inflammation characterized by polymorphonuclear cell infiltration when administered subcutaneously and inducing in vitro polymorphonuclear cell chemokinesis, while lacking the ability to suppress the activity of the anabolic enzyme lipoprotein lipase, cause the cytotoxicity of cachectin/TNF-sensitive cells, stimulate the blastogenesis of endotoxin-resistant C3H/HeJ thymocytes, or induce the production of cachectin/TNF by primary thioglycollate-elicited mouse macrophage cells. A particular inflammatory cytokine MIP-1 has been isolated and has been found to comprise a peptide doublet of similar molecular weights of about 8,000 daltons, and to show a pI of about 4.6. The doublet has been resolved into its component peptides, MIP-1.alpha. and MIP-1.beta. for which distinct cDNA's have been cloned and sequenced. Diagnostic and therapeutic utilities are proposed, and testing procedures, materials in kit form and pharmaceutical compositions are likewise set forth.

Macrophage-derived inflammatory mediator (MIP-1.alpha. and MIP-1.beta.)

Composition comprising antibody to macrophage-derived inflammatory

Method for measuring the binding sites for macrophage-derived

Engineered cell surface receptors are described that are constitutively active in the absence of the cytokine, hormone or molecule that normally activates the receptor. Receptors that constitutively signal are generally created by engineering the receptor to form multimers at the cell surface. Disclosed are various DNA, protein and cellular compositions and methods of making and using such constitutively active receptors. Particular examples are fusion proteins in which the stem, transmembrane domain and cytoplasmic domain are derived from a TNF receptor, and the extracellular, multimerizing domain is derived from an erythropoietin receptor. Transfection of such fusion protein constructs into cells is shown to result in a strong cytotoxic effect.

Modified receptors that continuously signal

Macrophage-derived inflammatory mediator (MIP-1 .alpha. and MIP-1 .beta.)

Disclosed are novel nucleic acid and peptide compositions comprising a constitutively-expressed CC chemokine. Also disclosed are methods of use for MIP-1.gamma. amino acid sequences and the DNA segments which encode them in the stimulation of an immune response, the production of limited pyrexia, the treatment of proliferative cell disorders and T-cell mediated diseases, and the prophylaxis of bacterial sepsis in an animal.

DNA encoding macrophage inflammatory protein-1.gamma.

Antibodies to an inflammatory cytokine are disclosed. The inflammatory cytokine has been isolated from cells that have been incubated with a stimulator material and comprises a protein that is capable of binding to heparin, inducing localized inflammation characterized by polymorphonuclear cell infiltration when administered subcutaneously and inducing in vitro polymorphonuclear cell chemokinesis, while lacking the ability to suppress the activity of the anabolic enzyme lipoprotein lipase, cause the cytotoxicity of cachectin/TNF-sensitive cells, stimulate the blastogenesis of endotoxin-resistant C3H/HeJ thymocytes, or induce the production of cachectin/TNF by primary thioglycollate-elicited mouse macrophage cells. A particular inflammatory cytokine MIP-1 has been isolated and has been found to comprise a peptide doublet of similar molecular weights of about 8,000 daltons, and to show a pI of about 4.6. The doublet has been resolved into its component peptides, MIP-1.alpha. and MIP-1.beta. for which distinct cDNA's have been cloned and sequenced. Diagnostic and therapeutic utilities are proposed, and testing procedures, materials in kit form and pharmaceutical compositions are likewise set forth.

Growing community of inventors

Dallas, TX, United States of America

Bruce A Beutler