Duke University

The Johns Hopkins University

Michael R Zalutsky

Ganesan Vaidyanathan

Martin Gilbert Pomper

Darell D Bigner

Ronnie Charles Mease

Sangeeta Ray

Vivek Kumar

Oscar Rodolfo Pozzi

Acharan S Narula

Small molecule radiohalogenated PSMA inhibitors and metal complexes thereof and their use in radioimaging and radiotherapy for treating PSMA-related diseases, including prostate cancer, are disclosed. The combination of small molecule radiohalogenated PSMA inhibitors with a competitive PSMA ligand for reducing off-target accumulation of the radiohalogenated PSMA inhibitor also is disclosed.

PSMA targeted radiohalogenated urea-polyaminocarboxylates for cancer radiotherapy

Small molecule radiohalogenated PSMA inhibitors and metal complexes thereof and their use in radioimaging and radiotherapy for treating PSMA-related diseases, including prostate cancer, are disclosed. The combination of small molecule radiohalogenated PSMA inhibitors with a competitive PSMA ligand for reducing off target accumulation of the radiohalogenated PSMA inhibitor also is disclosed.

Prosthetic compounds are disclosed that are effective for radiolabeling biomolecules with 18F. Representative biomolecules include antibodies (e.g., monoclonal antibodies (mAbs) and nanobodies (sdAbs)), antibody fragments, and peptides that may have an affinity for particular types of cells, such as cancer cells. The prosthetic compounds effectively address the art-recognized difficulties associated with the retention of radioactivity within the targeted cells, due to internalization of the biomolecule, followed by proteolytic degradation. Representative prosthetic compounds include (i) a succinimidyloxycarbonyl moiety, (ii) a radioactive moiety bearing 18F, and (iii) a charged moiety, i.e., a moiety that is charged under the physiological conditions of the internal cell environment.

Prosthetic compounds for labeling internalizing biomolecules

Oxidants (e.g., N-chlorosuccinimide) can be used to stabilize &#x3b1;-particle emitters (e.g.,At) in solution, prior to their subsequent reaction to form &#x3b1;-particle emitter labeled compounds (e.g., a radiolabeled pharmaceutical or a radiolabeled pre-cursor used to prepare it). In particular, the use of an oxidant has been found to maintain the &#x3b1;-particle emitter in a chemical form that facilitates this reaction, which may involve a number of possible mechanisms including electrophilic substitution, nucleophilic substitution, complexation, exchange, or metallic bonding. Compounds labeled with &#x3b1;-particle emitters in this manner have wide-ranging therapeutic applications, particularly in the treatment of cancer.

Stabilized compositions and methods for radiolabeling pharmaceuticals with alpha-particle emitters

Antibodies to cell surface ligands such as EGFRvIII can be used to therapeutically or diagnostically deliver a radiolabel to tumor cells with high selectivity. The utility of radioconjugated internalizing antibodies is limited, however, by release of the label and its reuptake into normal cells. The invention provides new technology for radioconjugation of internalizing antibodies which reduces the release of label and improves retention of radioconjugated antibodies in lysosomes, where radiation is more effectively and selectively delivered to the nucleus of tumor cells.

Radioconjugation of internalizing antibodies

Methods of treating solid and cystic tumors are disclosed. The method comprises administering to a subject afflicted with a cystic tumor an antibody which binds to tenascin in a therapeutically effective amount. The administering step is carried out by depositing the antibody in the cyst cavity of the cystic tumor. For solid tumors, disclosed is a method involving first, removing a solid tumor from a solid tissue organ of an afflicted subject; then forming an enclosed resection cavity in the organ of the subject at the location from which the solid tumor was removed; and then administering to the subject an antineoplastic agent by depositing the antineoplastic agent in the resection cavity. Particularly preferred for carrying out the foregoing is the monoclonal antibody 81C6 and antibodies which bind to the epitope bound by monoclonal antibody 81C6.

Method of treating brain tumors expressing tenascin

Methods of treating solid or cystic tumors are disclosed. The method comprises administering to a human subject afflicted with a tumor an antibody in a therapeutically effective amount, wherein the antibody is monoclonal antibody Me1-14 or an antibody which binds to the epitope bound by monoclonal antibody Me1-14, and wherein the Fc receptor of the antibody is deleted. When the tumor is a brain tumor, the antibody may be administered by intrathecal injection. If the brain tumor is a cystic brain tumor, and the administering step may be carried out by depositing the antibody in the cyst cavity of the cystic brain tumor. Particularly preferred is a monoclonal antibody Me1-14 F(ab').sub.2 fragment coupled to .sup.131 I.

Methods of treating melanomas and gliomas with monoclonal antibody Me1-14

Compounds of the formulae, ##STR1## are provided where L is a linking group of the formula, ##STR2## is --Sn(n--C.sub.4 H.sub.9).sub.3 or --Sn(CH.sub.3).sub.3, HgCl or --N.sub.2.sup.+ ; R is hydrogen, methyl, mono-, di- or oligosaccharide; and R' is methyl. The compounds are site-specifically halogenated or radiohalogenated at the A group and coupled with macromolecules such as monoclonal antibodies, peptides or other proteins.

Growing community of inventors

Chapel Hill, NC, United States of America

Michael R Zalutsky