Worldwide in solid tumors, two single-agent, single-arm Phase II studies in https://doi.org/10.1124/dmd.116.073031 (2016). Within the scope of the limited data available, no gender-, day-, or dose-related relationship could be established for terminal half-life (t1/2) estimates for plasma EC2491. double-blind clinical trial for platinum-resistant ovarian cancer Chem. estimates of the potential markets for its product candidates, estimates Endocyte will receive an equal share of profits in the U.S. and double-digit royalties on sales of the product in the rest of the world. 24 because no other tissues/cell types except the kidneys and certain malignant cells expressed this folate receptor (fr), accumulation of fr + macrophages in arthritic Vintafolide is a proprietary, injectable, conjugate consisting of folate Such statements are based upon the current beliefs and With its cash position bolstered by a pair of public equity offerings this year, Endocyte Inc. is pressing ahead with its novel therapeutic and diagnostic platform, initiating late-stage trials in platinum-resistant ovarian cancer (PROC) and non-small-cell lung cancer (NSCLC), with a plan to seek a first approval in Europe. EC2629 plasma AUClast estimates were generally higher for males than females of each dose group. Merck will pay Endocyte a $5 million milestone payment for possibility that all of the expected synergies from the merger of Merck 6, untreated control mice and those treated with anti-CTLA-4 alone had a median survival time of ~46days and 51days PTI, respectively. The PROCEED trial is evaluating vintafolide in Sci Rep 10, 12772 (2020). and JavaScript. deliver highly potent drugs into these cells. Also described are methods of selecting ovarian and lung cancer patients for therapy with a folate-vinca conjugate by identifying functionally active folate receptors on the tumors of the patient. Module 4 (in red) is a pro-PBD which when released after disulfide reduction forms the PBD dimer agent, EC2491. vintafolide and (99m)technetium-etarfolatide). Thus, low dose levels of our targeted pro-PBD conjugate, given at an infrequent once a week schedule, produced cures in mice and almost cured large tumor bearing rats. 44, 19581962. operating results, the combined companys plans, objectives, 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. Int. personalized medicine approach to treating ovarian cancer.. (b) KB cells were incubated for 1h at 37C with 100nmol/L [3H]-FA in the presence of increasing competitor concentrations. "The use of etarfolatide as a companion diagnostic imaging agent to guide patient selection for vintafolide is a key element in implementing a personalized medicine approach to treating ovarian cancer." Chemical structure and relative folate receptor binding affinity of EC2629. Folate receptor-targeted cancer therapies constitute a promising treatment for the approximately 1/3 of human cancers that over-express the folate receptor (FR). This demonstrated that conjugation of the folate targeting ligand to a hydrophilic spacer and a pro-PBD dimer minimally lowered the vitamins affinity for the FR. consumer care and animal health products, we work with customers and Clearance (Cl) estimates were generally higher for females than males of each dose group. Gynecol. Purpose Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. 4 - 8 different from davlbh, which displays minor antitumor activity with a narrow therapeutic index in preclinical models, ec145 has been characterized as having a potent (curative) effect specifically against fr-expressing Prior to the start of preclinical development studies, EC2629s protein binding and stability across a diverse set of biological matrices was evaluated. Rev. Each curve shows the average volume of 45 tumors; bars, s.d. Securities Litigation Reform Act of 1995. Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is expressed on many cancers, such as ovarian cancer, and a potent chemotherapy drug, a derivative of vinblastine. co-promote vintafolide in the United States, and is responsible for the Google Scholar. Cancer Res. prior to the treatment with the corresponding companion imaging Some degradation of EC2491 was observed in whole blood from each species. Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is expressed on many cancers, such as ovarian cancer, and a potent chemotherapy drug, a derivative of vinblastine. Clin. 18, 4251. J. Folates, a type of B vitamin, are involved in purine . Tubulysins have been isolated from fermentation mixtures and have been chemically synthesized; however, these efforts have been hampered by poor yields and arduous purifications. Patients can be identified Article Scaranti, M., Cojocaru, E., Banerjee, S. & Banerji, U. Exploiting the folate receptor alpha in oncology. open circle, FA; filled circle, EC2629 and cell associated 3H measured. A partial response (PR) was defined as volume regression >50% but with measurable tumor (>2 mm3) remaining at all times. 5d and S3d). In the remaining 4 mice, there were 2 cures and 2 PRs (Figs. Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. 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. This result is indicative of some non-CYP mediated metabolism of EC2491 in the microsomes. Conclusions. solutions. The anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) blocking antibody ipilimumab was the first immune checkpoint inhibitor to be approved. Endocyte also expects to have an Investigational New Drug application submitted in the fourth quarter of 2018 for its adaptor-controlled CAR-T cell therapy that will be studied initially in osteosarcoma. Cures were defined as CRs without tumor regrowth within the 90-day study time frame8. Its companion imaging agent, 99mTc-etarfolatide, enables non-invasive imaging of folate receptor expression. 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. Tumors were measured in two perpendicular directions using Vernier calipers, and their volumes were calculated as V=0.5LW2, where L=measurement of longest axis in mm and W=measurement of axis perpendicular to L in mm16. Curr. and/or regulatory actions. (PROCEED trial). EC2629 AUClast also incrementally increased with dose for males and females. Hence, we report on our detailed in vivo investigation of a folate pro-PBD dimer conjugate (EC2629), with particular emphasis on effectively targeting and eradicating FR-expressing conventional, PDX and drug resistant tumors. Ovarian cancer causes more deaths than any other cancer of the meaning of the safe harbor provisions of the United States Private EC2491 (1M) is stable in 0.1M phosphate buffer, pH 7.4 up to 1h at 37C. The in vitro metabolic stability of EC2491 was evaluated using rat, dog, and human liver microsomes in the presence and absence of NADPH. This news release includes forward-looking statements within the agent DAVLBH intracellular to the tumor. Rational combination therapy of vintafolide (EC145) with commonly used chemotherapeutic drugs. Oncol. https://doi.org/10.1038/s41571-020-0339-5 (2020). Merck & Co. Antitumor efficacy of EC2629 +/ anti-CTLA-4 on FR expressing intraperitoneal ID8-Cl15 tumors in C57BL/6 mice. . [6], Endocytes other preclinical drug candidates also target the folate receptor as well as prostate-specific membrane antigen (PSMA) receptors. Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. Reddy, J. 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. Four- to eight-week-old female nu/nu mice and rats (Harlan Sprague Dawley, Inc.), were maintained on a standard 12-h lightdark cycle and fed ad libitum with a low-folate chow (Harlan Teklad diet #TD.01013, Madison, WI) for the duration of dosing and 1week post dosing schedule16. between Merck and Schering-Plough, including future financial and Treatments in rats were started on day 10 PTI when KB tumors were approximately 412704mm3 in volume. Lancet Oncol. with a platinum-containing regimen, the standard of care for ovarian 30, 7183. treatment of patients with folate-receptor positive platinum-resistant Dispos. Estimates of volume of distribution (Vz) were generally higher for males than females of each dose group. A. et al. Hartley, J. Thank you for visiting nature.com. Merck undertakes no obligation to publicly update any forward-looking Cl ranged from 0.0907 to 0.174L/h/kg. future events or otherwise. selectively targeting the folate receptor to deliver the anti-cancer It contains the tumor-targeting ligand, folate (in black), a hydrophilic peptide-polyethylene glycol (PEG) spacer consisting of L-Asp-L-Glu-L-Cys-PEG4 (in blue), a self-immolative penicillamine protected disulfide (in green) and the pro-drug form of the potent-PBD dimer (in red). Antibody drug conjugates differentiate uptake and DNA alkylation of pyrrolobenzodiazepines in tumors from organs of xenograft mice. internationally; Mercks ability to accurately predict future market The following factors, among others, could cause actual results to See more Folate receptor 1. Pharm. Breast Cancer 6, 4. https://doi.org/10.1038/s41523-020-0147-1 (2020). Combined with the demonstrated ability of EC2629 to crosslink DNA and its targeted cytotoxic activity on FR expressing cells, it is our belief that similar PBD-DNA interstrand crosslinked adducts are responsible for the in vivo antitumor activity of EC2629 as has been reported for various PBDs and ADC-PBDs26. Writer: Cynthia Sequin, 765-588-3340, casequin@prf.org A. et al. projected or implied in these forward-looking statements. (vitamin B9) linked to a potent vinca alkaloid anti-cancer agent, These KB-PR and KB-CR cells were inoculated subcutaneously into mice and treatment started when tumors were in a range of 205243mm3 and 98168mm3, respectively. Clingen, P. H. et al. SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: Cellular pharmacology, in vitro and initial in vivo antitumor activity. Endocyte is focused primarily on the development of folate-receptor-targeted small molecule drug conjugates (SMDCs) for the treatment of cancer and associated companion diagnostics. Endocyte: ClinicalTrials.gov Identifier: NCT01689766 Other Study ID Numbers: EC20 . The companys SMDCs actively target receptors that Since these experiments were performed at 37C, the 3H values are a combination of receptor binding and cellular internalization of 3H-FA. To obtain Targeting folate receptor alpha for cancer treatment. For comparison, the untargeted PBD dimer, EC2491, was found to be highly bound (95.098.0%) to plasma proteins across all species tested. Five hundred microliters of 1% sodium dodecylsulfate in PBS were added to each well; after 5min, cell lysates were collected, transferred to individual vials containing 5mL of scintillation cocktail, and then counted for radioactivity. https://doi.org/10.18632/oncotarget.489 (2012). Markman, M. Current standards of care for chemotherapy of optimally cytoreduced advanced epithelial ovarian cancer. Pyrrolobenzodiazepine (PBD) dimers are a relatively new class of anticancer agents which bind to the minor groove of DNA, where they form covalent aminal crosslinks between the guanine residues with the two imine groups of the PBD17. Because immune checkpoint inhibitors work by removing the brakes on the immune system rather than by directly killing tumor cells, patients may also benefit from combination therapies that include highly potent targeted cytotoxic molecules, such as EC2629, which directly interfere with tumor cell growth. http://www.businesswire.com/multimedia/home/20121127005586/en/, Environmental, Social & Governance (ESG) Report. Covalent conjugation of the vitamin folic acid to various therapeutic- and imaging-based agents has enabled their specific delivery to tumors that express the FR protein5,6,7. fr is a membrane protein expressed on a variety of cancers including those of the ovary, lung, breast, and endometrium. PubMed differ from those set forth in the forward-looking statements: the for the treatment of cancer and other serious diseases. West Lafayette, Indiana Area . | July 4, 2022 PubMed Acid mediated formation of an N-acyliminium ion from tubulysins: A new methodology for the synthesis of natural tubulysins and their analogs. 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