Neorx Corporation

Gowsala P Sivam

Paul G Abrams

A Charles Morgan, Jr

Alton C Morgan, Jr

Vivekananda M Vrudhula

There is disclosed charge-modified conjugates comprising a targeting protein bound to a therapeutic or diagnostic agent. Charge-modifying a conjugate to cause an acidic shift in the isoelectric point results in prolonged serum half-life upon in vivo administration and is useful to accumulate a therapeutic agent at the target site. Conversely, charge-modification to cause a basic shift in the isoelectric point of the conjugate reduces serum half-life upon in vivo use for diagnostic imaging purposes and results in higher target-to-background ratios.

Alteration of pharmacokinetics of proteins by charge modification

Targeting substance-diagnostic/therapeutic agent conjugates joined by stabilized Schiff base or hydrazone linkages are disclosed. In addition, slow release carrier-drug pharmaceuticals are described. The diagnostic and therapeutic conjugates and pharmaceuticals of the present invention provide certain advantages relating to in vivo administration, including controlled release of the active agent at a target site.

Targeting substance-diagnostic/therapeutic agent conjugates having

Conjugates of trichothecenes and agents that bind to a defined population of cells are disclosed. Preferred are conjugates of trichothecene molecules with polyclonal or monoclonal antibodies or fragments thereof that recognize antigens that are present only on tumor cells or are augmented in their expression on tumor cells as compared to normal tissues. Trichothecene molecules are coupled to the agent through non-covalent and covalent linkages, such as peptide bonds, disulfide bonds, thioester bonds, or thioether bonds. A method for inhibiting the growth and metabolism of antigen-positive cells is also disclosed.

Trichothecene conjugates

Conjugates comprising a therapeutically effective proteinaceous active moiety linked to an albumin moiety which exhibit enhanced serum half-life and stability properties are disclosed. The conjugates may additionally comprise targeting moieties to facilitate selective localization of the active moiety at a target site. Conjugates of the present invention comprising an albumin moiety additionally exhibit reduced toxicity, yet maintain a high degree of selectivity and potency.

Conjugates having improved characteristics for in vivo administration

Method for producing an immunoconjugate comprising the steps of reacting a toxin or protein with a heterobifunctional reagent having the following general formula: ##STR1## where R.sub.1 is: ##STR2## where n=1 to 10; and where R.sub.2 is selected from the group consisting of o- and p-nitrophenyl, 2-chloro-4-nitrophenyl, cyanomethyl, 2-mercaptopyridyl, hydroxybenztriazole, N-hydroxysuccinimide, trichlorophenyl, tetrafluorophenyl, 2-fluorophenyl, 4-fluoropheyl, 2,4-difluorophenyl, o-nitro-p-sulfophenyl, N-hydroxyphthalimide, N,N-diethylamino, N-hydroxypyrrolidone, tetrafluorothiophenyl, and 2,3,5,6-tetrafluorophenyl, under reactive conditions, thereby forming a derivatized toxin or protein. The derivatized toxin or protein is separated from the reaction mixture and combined with an antibody or antibody fragment under reactive conditions, such that at least one native disulfide bond is reduced to produce at least one thiol group, capable of forming a thioether bond between said thiol group and the maleimide group of said derivatized toxin, or protein thereby forming an immunoconjugate. The preferred heterobifunctional linking group is succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

Immunoconjugates joined by thioether bonds having reduced toxicity and

Conjugates of trichothecenes and agents that bind to a defined population of cells are disclosed. Preferred are conjugates of trichothecene molecules with polyclonal or monoclonal antibodies or fragments thereof that recognize antigens that are present only on tumor cells or are augmented in their expression on tumor cells as compared to normal tissues. Trichothecene molecules are coupled to the agent through non-covalent and covalent linkages, such as peptide bonds, disulfide bonds, thioester bonds, or thioether bonds. Methods for reducing intoxification in a recipient of a trichothecene and an agent and for producing a trichothecene conjugate with improved solubility are also disclosed.

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Edmonds, WA, United States of America

Gowsala P Sivam