soblidotin and Kidney-Neoplasms

Metastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigen-dependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G2-M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibody-conjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no chemotherapeutic options.

Topics: Animals; Antigens, CD; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; CD27 Ligand; Cell Cycle; Humans; Immunoconjugates; Immunohistochemistry; Kidney Neoplasms; Lymphocyte Activation; Membrane Proteins; Mice; Mice, Nude; Microtubules; Oligopeptides; Phenylalanine; RNA, Messenger; Tumor Necrosis Factors; Xenograft Model Antitumor Assays

It has been revealed that chemotherapy using DNA-damaging agents and radiotherapy were influenced by the p53 status of tumors; however, p53 status did not influence chemotherapy using antimicrotubule agents. To elucidate whether a novel antimicrotubule agent, TZT-1027, is influenced by the p53 status of tumors, the authors investigated the sensitivities of specimens obtained from patients with nonsmall cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC) to various anticancer agents, including TZT-1027, and the status of the p53 gene in those specimens.. Twenty-nine NSCLC specimens and 22 RCC specimens were analyzed for their sensitivity to various anticancer agents and their p53 status. Sensitivities of the specimens to nine anticancer agents were determined by flow cytometric analysis. To determine p53 status, polymerase chain reaction amplification with primers for exons 5--9 was conducted, and the products were subjected to single-strand conformation polymorphism analysis.. In the NSCLC specimens, anticancer agents, including TZT-1027, showed strong antitumor activity against 50--75% of specimens with the wild type p53 gene. TZT-1027 showed strong antitumor activity against 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 16--28% of specimens. In RCC specimens, TZT-1027 showed potent antitumor activity in 29% of specimens with the wild type gene, and DNA-damaging agents showed such activity in 6--18% of specimens. TZT-1027 showed strong antitumor activity in 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 0--20% of specimens.. We found evidence to suggest that TZT-1027 was influenced less by the p53 status of specimens than DNA-damaging agents. Therefore, TZT-1027 is expected to show similar antitumor activity against tumors with a loss of p53 function as well as those with normal function of p53 in clinical fields.

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; DNA Damage; Female; Genes, p53; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Oligopeptides; Polymerase Chain Reaction; Tumor Cells, Cultured