Thus, the effect of protein binding on the bioavailable portion of EC2629 in circulation should be quite similar across species. Pharm. EC2491 was stable in rat, mouse, and dog plasma for greater than 24h. In whole blood analysis, EC2629 was most stable in mouse and human blood, with no observed degradation over the experimental time interval. The Cmax for plasma EC2629 increased with dose, and this increase was generally dose-proportional. Tumor fragments were harvested from host animals and implanted into 612weeks old female athymic nude mice (Crl:NU(NCr)-Foxn1nu). An estimated 80 percent of platinum-resistant ovarian cancer Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. The samples were mixed, centrifuged, and 100L of supernatant was transferred to a new plate prior to LCMS/MS analysis. Targeting folate receptor alpha for cancer treatment. The company was founded in 1996 and is based in West Lafayette, Indiana. Samples were extracted and analyzed using fit-for-purpose bioanalytical methods. 3c and S1c). In the ST040 endometrial and ST070 ovarian cancer models, EC2629 was evaluated at 0.27mol/kg, BIW2weeks in comparison with paclitaxel at 15mg/kg, SIW2weeks. Antitumor (a, c, e) and weight change (b, d, f) effects of EC2629 (a, b, c, d) and SJG-136 (e, f) on FR expressing KB tumor nu/nu mice (a, b, e, f) and rat (c, d) models. medical need. The folate receptor is a glycoprotein that is over-expressed in many types of cancer cells but it is only minimally distributed in normal tissues . 50L aliquots were withdrawn at various time points and mixed with internal standard, EC3044 (Endocyte) in acetonitrile. In the meantime, to ensure continued support, we are displaying the site without styles Worldwide unavailability of PLD, regulatory issues or other factors); risks that Endocyte: ClinicalTrials.gov Identifier: NCT01689766 Other Study ID Numbers: EC20 . Hence, the activity of EC2629 against this model was assessed by intravenously treating mice with 0.3mol/kg and rats with 0.15mol/kg following a once a week (SIW), 2-week schedule. PBD compounds have been tested against a variety of tumors including ovarian cancer, SCLC (small cell lung cancer), and AML (acute myeloid leukemia). differ from those set forth in the forward-looking statements: the The four PDX models chosen for this study were shown to be strongly positive for FR staining by a FR IHC assay (Biocare Medical) at START. Both the therapeutic and diagnostic imaging agent have been granted orphan drug status in Europe. Cheung, A. et al. http://www.businesswire.com/multimedia/home/20121127005586/en/, Environmental, Social & Governance (ESG) Report. Therefore, we present EC2629 as a promising first-in-class SMDC comprising a potent DNA crosslinking pharmacophore for the treatment of FR-positive tumors. This demonstrates that EC2629 acts as an inactive pro-drug with undetectable DNA binding ability until it is reduced to release the pro-PBD dimer with subsequent conversion to the active DNA crosslinking molecular form. EC2629 in the presence of DTT (reduction to cleave the disulfide bond resulting in the formation of the active PBD dimer, EC2491) displayed a concentration-dependent increase in fluorescence, while intact EC2629 showed background fluorescence at all concentrations (Fig. ZERO BIAS - scores, article reviews, protocol conditions and more . Sci. Curr. The folate receptor (FR) is a cell surface receptor that is overexpressed by many primary and metastatic cancers, including ovarian, lung and breast cancers1,2,3,4. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300nmol/kg) following a convenient once a week schedule. 2590 Background: FolateImmune is a folate-receptor (FR)-targeted immunotherapy that induces an immune response against tumor cells by marking tumor cells with a folate-hapten conjugate targeted to over expressed FR in renal cell carcinoma. ovarian cancer in combination with pegylated liposomal doxorubicin Rapidly dividing cancer cells . Name of the organization that made the acquisition, Stock ticker symbol (e.g. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the recent global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the companys ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the companys patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. 3H-thymidine was purchased from Moravek Biochemicals, Brea, CA. MedChemExpress References: PMID: 21974954 Tubuylsins are extremely potent cytotoxic agents which inhibit tubulin polymerization and lead to cell cycle arrest and Apoptosis. Upon entering a targeted cell, endosomal reductive cleavage of the disulfide bond, fragmentation of the linker system and further spontaneous condensation should result in formation of the potent PBD molecule. https://doi.org/10.1038/s41598-020-69682-9, DOI: https://doi.org/10.1038/s41598-020-69682-9. Both, dexamethasone-treated rat, and rifampin-treated dog liver microsomes showed more rapid metabolism of EC2491 than their corresponding corn-oil treated controls, indicating that CYP3A induction could result in faster metabolism of EC2491 in rats and dogs, and potentially humans. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Figure7b depicts the stability of 1M EC2491 in these CYP3A induced microsomes in the presence of NADPH. and Schering-Plough will not be realized, or will not be realized within selection for vintafolide is a key element in implementing a data from its clinical trials may not be indicative of subsequent Assaraf, Y. G., Leamon, C. P. & Reddy, J. ID8-Cl15, a mouse epithelial ovarian cancer cell line was transfected to express high levels of murine FR. Med. Module 3 (in green) is a bio-cleavable, self-immolative protected disulfide-based linker system. [2] Patients can be identified Google Scholar. Through our prescription medicines, vaccines, biologic therapies, and Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate which goes through an intramolecular ring-closing reaction to form the second diazepine ring of the cytotoxic PBD dimer, EC249124. Mice and rats were divided into two groups each and treatments started when the tumors had reached the 111168 mm3 (mice) or 411704 mm3 range (rats). Cures were defined as CRs without tumor regrowth within the 90-day study time frame8. These results show that EC2629 was equally active on small as well as large tumors and also in both the mouse and rat species. Individual tumor response endpoints were reported in terms of tumor volume change. Endocyte, Inc., 3000 Kent Ave., Suite A1-100, West Lafayette, IN, 47906, USA, Joseph A. Reddy,Melissa Nelson,Christina Dircksen,Marilynn Vetzel,Theresa Johnson,Vicky Cross,Elaine Westrick,LongWu Qi,Spencer Hahn,Hari Krishna Santhapuram,Garth Parham,Kevin Wang,Jeremy F. Vaughn,Albert Felten,Michael Pugh,June Lu,Patrick Klein,Iontcho R. Vlahov&Christopher P. Leamon, You can also search for this author in Endocyte intends to Merck is known as MSD outside the United States and Canada. https://doi.org/10.1158/0008-5472.CAN-03-2941 (2004). PubMed worldwide. See more Folate receptor 1. Lancet Oncol. A majority of ovarian cancer patients receive a first-line combination regimen that comprises of a taxane and a platinum drug. Hochhauser, D. et al. Drugs 9, 12771286 (2008). Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Folate receptor expression, and thus macrophage activation, can clearly be demonstrated in vivo, in small animal models of osteoarthritis using the new 111 In-folate conjugate with specific binding to the folate receptor. caused by competition, adverse events, patient enrollment rates, The DNA solution was then heat denatured at 104C for 5min, rapidly cooled on ice for 5min and fluorescence re-measured. of the breast, lung, and blood; EC0225, a targeted chemotherapy drug; BMS753493, a folate-targeted anti-cancer therapy drug; EC0434 to target folate receptor positive tumors; and EC0305, an anti-cancer therapy drug. Endocyte's initial folate-receptor programs, vintafolide (the drug) and etarfolatide (the diagnostic) for the treatment of ovarian cancer, are currently being evaluated by the European Medicines . prior to the treatment with the corresponding companion imaging combination with PLD compared to PLD plus placebo for the treatment of Animals in the control groups received no treatment. DTPA (diethylenetriaminepentaacetic acid-ethylenediamine- -folate) (a generous gift from Endocyte, Inc) (Wang et al., 1997, Mathias CJ and Green MA, 1998). This should effectively block the imine moiety and prevent the intact molecule from alkylating and crosslinking DNA. CTLA-4 is a key negative regulator of T cell activation, and CTLA-4-blocking antibodies have been shown to enhance the antitumor activity of chemotherapy33. Ovarian cancer standard of care: Are there real alternatives?. Development and Validation of a UPLC-MS/MS Method for the Novel Folate-Targeted Small Molecule Drug Conjugate EC1456 and its . In 2012 marketing rights were acquired by Merck for $120 million in an upfront payment and up to $880 million in milestone payments. As previously confirmed in rodents as well as in human clinical studies, EC17 penetrates solid tumors within minutes and . Writer: Cynthia Sequin, 765-588-3340, casequin@prf.org Other Names: folate-fluorescein conjugate; folate-hapten conjugate Endocyte, Inc., a biopharmaceutical company, develops receptor-targeted therapeutics to treat cancer and autoimmune/inflammatory diseases. In conclusion, EC2629 displays favorable biological properties including i) high affinity for the FR target, ii) sufficient stability in biological matrices, iii) highly potent and FR-specific cytotoxic activity, and iv) superior antitumor effect across numerous FR-expressing conventional, resistant and PDX tumor models following infrequent low dose schedules. folate-receptor positive platinum-resistant ovarian cancer. Plasma ultrafiltration was used for determination of free and protein bound fractions of EC2629 and EC2491. As shown in Fig. 26, 13151323. 5c and S3c, paclitaxel only showed modest tumor growth delay in the ST040 model with no SDs in that cohort, whereas EC2629 displayed stronger anti-tumor effect with two SDs and three PRs among the 7 mice (Fig. The company was formed based on technology developed by Philip Low (the company's CSO), and Christopher Leamon, PhD, the companys VP of research. 6, 15181525. 1b). https://doi.org/10.1038/s41571-020-0339-5 (2020). open circle, untreated controls; filled circle, anti-CTLA-4 antibody 0.25mg/dose, BIW, 5 doses; filled square, EC2629, 0.1mol/kg, BIW6 doses; filled diamond, EC2629+ anti-CTLA-4 antibody. Endocyte's Investigational Diagnostic Imaging Agent Etarfolatide Identifies Ovarian Cancer and Non-Small Cell Lung Cancer Patients Most Likely to Benefit From Folate Receptor-Targeted Treatment . . statement, whether as a result of new information, future events or https://doi.org/10.1016/j.clbc.2017.03.007 (2017). This agent was found to be extremely potent with an in vitro IC50 ~100 lower than folate SMDCs constructed with various microtubule inhibitors. Provided by the Springer Nature SharedIt content-sharing initiative. PubMed desacetylvinblastine hydrazide (DAVLBH). double-blind clinical trial for platinum-resistant ovarian cancer Antitumor effects of EC2629 on FR expressing KB-PR (a) and KB-CR (b) tumors in nu/nu mice. Increased macrophage activity only plays a role in the groove model of osteoarthritis when applied in a high-fat diet induced dysmetabolic condition, which is in . If conditional marketing authorization is granted, data from the Proceed trial will subsequently be submitted to serve as the confirmatory data required to convert conditional approval to regular marketing authorization for EC145 and EC20. projected or implied in these forward-looking statements. Pharm. The PROCEED trial is evaluating vintafolide in Under terms of the development deal Endocyte will primarily be responsible for funding and completing the Proceed trial, and Merck will take on all other development activities and costs. Patient derived xenograft (PDX) studies were performed at South Texas Accelerated Research Therapeutics (START, San Antonio, TX). Such regimens are intended to benefit from the non-overlapping tissue toxicity combined with their antitumor activity against differentially resistant cancer cell clones. Additional factors that could cause results to differ There was no apparent dose-related effect on Vz. Conjugates (SMDCs) and companion imaging diagnostics for personalized Since most FR positive tumors can reach 4106 receptors/cell, the amount of deliverable PBD-dimer should be well above the required threshold. Cl ranged from 0.0907 to 0.174L/h/kg. [1] The original president and CEO, Ron Ellis,[1] was succeeded by Mike Sherman, who held a CFO position at the company before this change in June 2016. Dose response activity and specificity of EC2629 were evaluated in vitro. Active, Closed, Last funding round type (e.g. Leamon, C. P., You, F., Santhapuram, H. K., Fan, M. & Vlahov, I. R. Properties influencing the relative binding affinity of pteroate derivatives and drug conjugates thereof to the folate receptor. well. Each curve shows the average volume of 37 tumors; bars, s.d. Each curve shows the average volume of 35 tumors/animals; bars, s.d. In vivo structural activity and optimization studies of folate-tubulysin conjugates. Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. 25, 852858. Further, EC2629-treated animals did not lose any significant weight (Figs.