monomethyl-auristatin-e and Prostatic-Neoplasms

Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer.. In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging.. Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent.. In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Neoplasm; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Neoplasm Staging; Neoplastic Cells, Circulating; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

Combined radiotherapy (RT) and chemotherapy are prescribed to patients with advanced prostate cancer (PCa) to increase their survival; however, radiation-related side effects and systematic toxicity caused by chemotherapeutic drugs are unavoidable. To improve the precision and efficacy of concurrent RT and chemotherapy, we have developed a PCa-targeted gold nanocluster radiosensitizer conjugated with a highly potent cytotoxin, monomethyl auristatin E, PSMA-AuNC-MMAE, for RT and chemotherapy of PCa. This approach resulted in enhanced uptake of NCs by PSMA-positive cancer cells, targeted chemotherapy, and increased efficacy of RT both

Topics: Cell Line, Tumor; Chemoradiotherapy; Gold; Humans; Male; Oligopeptides; Peptide Hydrolases; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77-85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (-)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.

Topics: Antigens, Surface; Cell Line, Tumor; Coordination Complexes; Glutamate Carboxypeptidase II; Humans; Male; Microsomes, Liver; Oligopeptides; Prostatic Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Novel nanomedicines have been engineered to deliver molecules with therapeutic potentials, overcoming drawbacks such as poor solubility, toxicity or short half-life. Lipid-based carriers such as liposomes represent one of the most advanced classes of drug delivery systems. A Monomethyl Auristatin E (MMAE) warhead was grafted on a lipid derivative and integrated in fusogenic liposomes, following the model of antibody drug conjugates. By modulating the liposome composition, we designed a set of particles characterized by different membrane fluidities as a key parameter to obtain selective uptake from fibroblast or prostate tumor cells. Only the fluid liposomes made of palmitoyl-oleoyl-phosphatidylcholine and dioleoyl-phosphatidylethanolamine, integrating the MMAE-lipid derivative, showed an effect on prostate tumor PC-3 and LNCaP cell viability. On the other hand, they exhibited negligible effects on the fibroblast NIH-3T3 cells, which only interacted with rigid liposomes. Therefore, fluid liposomes grafted with MMAE represent an interesting example of drug carriers, as they can be easily engineered to promote liposome fusion with the target membrane and ensure drug selectivity.

Topics: Animals; Cell Line, Tumor; Cell Survival; Humans; Liposomes; Male; Membrane Fluidity; Mice; NIH 3T3 Cells; Oligopeptides; Particle Size; Prostatic Neoplasms; Time Factors; Triglycerides

The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with 111In-mAbs and gamma counting or with 89Zr-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that 89Zr-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Humans; Immunoconjugates; Male; Membrane Proteins; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Oligopeptides; Oxidoreductases; Positron-Emission Tomography; Prostatic Neoplasms; Radioisotopes; Xenograft Model Antitumor Assays; Zirconium

Bone metastasis from primary prostate cancer leads to markedly diminished quality of life with poor long-term survival. Bone seeking treatment options are limited with adverse consequences on rapidly proliferating tissues such as bone marrow. In the present study, we seek to determine the bone-enriching capabilities of monomethyl auristatin E phosphate (MMAEp), a derivative of the potent antimitotic monomethyl auristatin E (MMAE).. The in vitro actions and mechanisms of cytotoxicity were assessed using cell viability, immunofluorescence, flow cytometry, and Western blot analysis. In vivo efficacy was determined using an intratibial xenograft mouse model of human prostate cancer and live animal imaging.. The half maximal inhibitory concentration (IC50) of MMAE and MMAEp was determined to be approximately 2 and 48 nM, respectively, in PC-3 and C4-2B cell lines. MMAEp retained the mechanism of action of MMAE in reducing microtubule polymerization and stalling cell cycle progression at the G2/M transition. MMAEp was able to bind hydroxyapatite in in vitro assays. MMAEp significantly reduced intratibial tumor growth compared to the vehicle control treatment.. MMAEp is an antimitotic compound that binds to calcium ions in the bone and inhibits prostate tumor growth in the bone. Prostate 76:1420-1430, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antimitotic Agents; Apoptosis; Bone Neoplasms; Calcium; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Durapatite; Humans; Ions; Male; Mice; Microtubules; Oligopeptides; Phosphates; Prostatic Neoplasms; Tibia; Tubulin Modulators; Tumor Burden; Xenograft Model Antitumor Assays