University of Texas System

Immunivest Corporation

Other

Board of Regents

Genentech, Inc.

Jonathan W Uhr

Ellen S Vitetta

Paul A Liberti

Leon W M M Terstappen

Galla Chandra Rao

Emilian V Racila

Maria-Ana Ghetie

Richard H Scheuermann

Victor F Ghetie

Louis J Picker

Gail Dianne Phillips

This invention discloses monoclonal antibodies (MAbs) which have little or no signaling activity as monomers become potent anti-tumor agents when they are converted into homoconjugates. The homoconjugates exert anti-growth activity by signaling G/Garrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and does not require an Fc portion. These conjugates are potent, anti-tumor agents.

Compositions and methods for homoconjugates of antibodies which induce growth arrest of apoptosis of tumor cells

A highly sensitive assay is disclosed which combines immunomagnetic enrichment with multiparameter flow cytometric and immunocytochemical analysis to detect, enumerate and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood and has a greater sensitivity than conventional PCR or immunohistochemistry by 1-2 orders of magnitude. In addition, the assay facilitates the biological characterization and staging of carcinoma cells.

Methods and reagents for the rapid and efficient isolation of circulating cancer cells

This invention discloses monoclonal antibodies (MAbs) which have little or no signaling activity as monomers become potent anti-tumor agents when they are converted into homoconjugates. The homoconjugates exert anti-growth activity by signaling G /G arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and does not require an Fc portion. These conjugates are potent, anti-tumor agents.

Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells

Disclosed are methods and compositions for the treatment of HIV infections through the specific elimination of cells which express HIV env determinants such as gp120. The compositions of the invention include toxin conjugates composed of a CD4 derived gp120 binding ligand conjugated to a toxin A chain moiety such as ricin A chain or deglycosylated ricin A chain. Where a therapeutic composition is desired, the conjugates are formed by means of a cross linker which includes a disulfide bond. Disulfide linkages are not crucial where non-therapeutic uses, such as antibody generation, is intended. In preferred aspects of the invention, conjugates incorporating shorter CD4 peptides, such as those incorporating amino acids 41-57 or 41-84 of CD4, are disclosed. Therapeutic amounts of conjugates composed of soluble CD4 or a CD4 peptide cross-linked to deglycosylated A chain by means of as SMPT linker is administered to an HIV infected patient so as to specifically eliminate HIV infected cells without exerting significant toxicity against uninfected or class II cells.

Therapeutic compositions comprising a CD4 peptide and methods of

The anti-tumor activity of a mixture of anti-CD22 and anti-CD19 immunotoxins is shown to be significantly enhanced in SCID/Daudi mice with disseminated human Daudi lymphoma. Unexpectedly identical enhancement was observed employing a combination of the anti-CD22 immunotoxin with unconjugated anti-CD19 antibodies. Thus combinations of an anti-CD22 immunotoxin and an anti-CD19 immunotoxin or antibody act synergistically and provide advantageous compositions and methods for immunotherapeutic treatment of various diseases including cancer and autoimmune disorders. Also disclosed is data indicating that certain anti-CD19 antibodies alone inhibit proliferation of CD19-positive cells by inducing cell cycle arrest.

Epitope-specific monoclonal antibodies and immunotoxins and uses thereof

Disclosed are methods for the identification and characterization of tumor cell types present within malignant populations, and novel methods of cancer treatment. Tumor cells in cell cycle arrest have been identified, purified and characterized according to their size, altered morphology, surface phenotype and expression of oncogenes. Tumor cell cycle arrest can be induced in mice lacking an immune system solely upon administration of anti-idiotype antibodies. Methods of manipulating specific signals from the cell surface to alter the malignant phenotype of transformed cells are disclosed, as are methods for either eliminating or specifically maintaining tumor cells in cell cycle arrest.

Method for identifying tumor cells in cell cycle arrest

Immunotoxin preparations are described in which the preparations are enriched for a single species of immunotoxin. Also described are methods for the preparation of the substantially purified immunotoxins (ITs). Also disclosed are methods for determining the most effective species of immunotoxin conjugates for treated diseases and pharmaceutical preparations for such treatments.

Methods and compositions concerning homogenous immunotoxin preparations

The present disclosure described an assay for screening monoclonal antibodies for their potential as highly cytotoxic immunotoxins. The assay involves treating cells with dilutions of the test antibody followed by a Fab fragment of a secondary antibody coupled to an A chain toxin ('indirect assay'). The cytotoxicity of the indirect assay is compared to that of the direct assay where the monoclonal antibody is coupled to an A chain toxin. Indirect and direct assays were carried out using 14 antibodies and a panel of 8 human and mouse cell types. The two assays showed virtually 100% correlation. The indirect assay, therefore, predicts the potency of a given monoclonal antibody to make an effective immunotoxin and should be useful in screening monoclonal antibodies for use as immunotoxins.

Methods for screening antibodies for use as immunotoxins

Highly specific antibodies directed against immunoglobulin determinants coupled to one or more toxin molecules provide antibody-toxin conjugates which are useful in selectively inhibiting the growth of target immunoglobulin generating cells. The antibody-toxin conjugate consists of an antibody specific for a selected immunoglobulin determinant including isotypic, allotypic or idiotypic variable determinants, coupled to one or more toxin molecules. Anti-idiotype toxin conjugates are provided which have specificity which distinguishes B cell tumor cells from normal B cells. Also disclosed is an antibody-toxin conjugate consisting of anti-IgD A chain. The antibody-toxin conjugate is used as a cell or tumor specific cytotoxic agent directed selectively against those cells expressing the corresponding immunoglobulin to which the antibody portion has specificity.

Anti-immunoglobulin toxin conjugates useful in the treatment of B cell

Compositions and methods for potentiating the cytotoxic activity of immunogotoxin conjugates are provided. The compositions of the present invention include a selective binding agent such as an antibody coupled to a toxin B chain moiety such as ricin B chain.

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Dallas, TX, United States of America

Jonathan W Uhr