This is indicative of CYP-mediated metabolism of EC2491. Cancer Res. EC131, a new folate receptor (FR)-targeted drug conjugate, was prepared by covalently attaching the vitamin folic acid (FA) to a potent microtubule-inhibiting agent, maytansinoid DM1, via an intramolecular disulfide bond. facts. operating results, the combined companys plans, objectives, Cancer Res. PubMed 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. 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. 15, 21402147. open circle, FA; filled circle, EC2629 and cell associated 3H measured. Lancet Oncol. meaning of the safe harbor provisions of the United States Private Folate is the natural ligand for the folate receptor [FR], but folic acid readily binds to FR too. support its product candidates, projected cash needs, and expected https://doi.org/10.1158/2159-8290.CD-18-0367 (2018). The In the ST502 model, eribulin mesylate did not display significant anti-tumor activity, producing one stable disease (SD) and one partial response (PR) among seven mice; whereas, EC2629 generated two PRs, two complete responses (CRs) and three cures among a different cohort of seven mice (Fig. and J.L. [1] Endocyte retained rights to the development and commercialization of etarfolatide. Blood 131, 387396. Briefly, 1105 FR-positive KB cells were seeded into each well of 24-well Falcon plates and allowed to form adherent monolayers overnight in FFRPMI/HIFCS. Antitumor efficacy of EC2629 +/ anti-CTLA-4 on FR expressing intraperitoneal ID8-Cl15 tumors in C57BL/6 mice. Cancer Res. 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. This structural feature was designed to further stabilize this SMDC during circulation by providing steric hindrance around the disulfide bond. Vlahov, I. R. et al. Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates. https://doi.org/10.1158/1078-0432.CCR-13-2423 (2014). Therefore, we present EC2629 as a promising first-in-class SMDC comprising a potent DNA crosslinking pharmacophore for the treatment of FR-positive tumors. Animals that were moribund (or unable to reach food or water) were euthanized by CO2 asphyxiation. For more information, visit www.endocyte.com. CAS & Thurston, D. E. Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: Is mechanism related to systemic toxicity?. Untreated control mice reached a tumor size of 1,500 mm3 by 2330days PTI (post tumor implant), whereas treatment with EC2629 led to 100% cures (Fig. Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. mp500348e_si_001.pdf (33.28 kb) Terms & Conditions Access videos, logos, photos, and infographics. https://doi.org/10.1021/acs.bioconjchem.7b00476 (2017). Since most FR positive tumors can reach 4106 receptors/cell, the amount of deliverable PBD-dimer should be well above the required threshold. Endocyte folate receptor targeted chemotherapeutic drug vintafolide Folate Receptor Targeted Chemotherapeutic Drug Vintafolide, supplied by Endocyte, used in various techniques. EC2629 in 0.9% sodium chloride (saline) was administered at the following dosages: Control0mg/kg/dose (Group 0); 0.05mg/kg/dose (Group 1); 0.1mg/kg/dose (Group 2); 0.25mg/kg/dose (Group 3); and 0.5mg/kg/dose (Group 5). https://doi.org/10.18632/oncotarget.9651 (2016). Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319 . Naumann, R. W. et al. 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. Patient tumor tissues were obtained with patients informed consent and PDX models were generated after multiple generations in mice. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. This clinical observation leads us to believe that a Folate SMDC with a more potent warhead, such as a PBD, may potentially increase the therapeutic benefit in patients with fewer than 100% FR positive lesions or in patients with generally lower tumor FR expression levels. Cells were incubated for 1h in triplicate wells at 37C and then rinsed 3 times with 0.5mL of PBS. Ann. Viability was assessed by measuring 3H-thymidine incorporation into trichloroacetic acid precipitable material. Generally, EC2629s anti-tumor activity in these PDX models was found to be independent of their sensitivity to standard-of-care chemotherapy regimens. folate-receptor positive platinum-resistant ovarian cancer. In the presence of NADPH male rat liver microsomes metabolize EC2491 rapidly such that only 2% of the compound remains in the incubation mixture at the end of 1h. Male dog and human liver microsomes metabolize EC2491 somewhat slowly (22% and 18% remaining at the end of 1h respectively). Rev. Folate receptor (FR) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. targeted therapies. Vintafolide, a folate-vinca alkaloid drug conjugate, is a folate receptor-targeted drug. 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. A. et al. The relative affinity of EC2629 was determined according to a previously published procedure35. It was therefore hypothesized that combining EC2629 with an immune checkpoint inhibitor may afford greater therapeutic efficacy compared to single-agent therapy. Folate receptor alpha is a protein that in humans is encoded by the FOLR1 gene. More particularly, the disclosure relates to using des-glutamyl folic acid analogs recognized by and selectively bound by folate receptors and other folate binding proteins and the use of such analogs for targeted delivery of diagnostic or therapeutic agents to folate-receptor . By submitting a comment you agree to abide by our Terms and Community Guidelines. Folate receptor (FR) expression in normal tissues is limited, while upregulation of FRs has been noted in several forms of human cancer ( 5, 6 ). These statements are based upon the current beliefs and expectations of the companys management and are subject to significant risks and uncertainties. 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. Med. United States, Canada, Europe and Asia. J.A.R. By continuing, you will be directed to a site intended only for residents of the United States and Canada. (vitamin B9) linked to a potent vinca alkaloid anti-cancer agent, We have sent a message to the email address you have provided, .If this email is not correct, please update your settings with your correct address. . 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. 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Each curve shows the average volume of 35 tumors/animals; bars, s.d. Anti-mouse CTLA-4 antibody (Clone UC10-4F10-11) was obtained from BioCell (West Lebanon, NH) All other common reagents were purchased from Sigma or other major suppliers. Chem. 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. The Cmax for plasma EC2629 increased with dose, and this increase was generally dose-proportional. Endocyte develops small molecule drug conjugate targeting the folate receptor. Breast Cancer 17, 544549. As a general measure of gross toxicity, changes in body weights were determined on the same schedule as tumor volume measurements. https://doi.org/10.1158/0008-5472.CAN-03-2941 (2004). Control tumors in rats reached the target tumor size of 15,000 mm3 by 2528days PTI, while EC2629-treated rats yielded 2 CRs and 1 PR (Fig. As presented above, EC2629s favorable biological performance against a variety of different tumor models provides support for potential clinical evaluation. open circle, untreated controls; filled triangles (a), paclitaxel, 20mg/kg, TIW2weeks (b) cisplatin, 3mg/kg, BIW2weeks; filled circle, EC2629, 0.5mol/kg, SIW2weeks. co-promote vintafolide in the United States, and is responsible for the Aiming to reduce the reported off-target toxicities of clinically tested PBD agents such as SJG-136, vadastuximab talirine and Rova-T, we have masked one of the highly reactive imines of PBD in EC262922. Ovarian cancer causes more deaths than any other cancer of the healthcare through far-reaching policies, programs and partnerships. Cancer Discov. Both vintafolide and etarfolatide have been granted orphan drug (PROCEED trial). Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. 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 Legal Name Endocyte, Inc. Stock Symbol NASDAQ:ECYT Company Type For Profit Contact Email info@endocyte.com Phone Number (765) 463-7175 Endocyte, Inc., a biopharmaceutical company, develops receptor-targeted therapeutics to treat cancer and autoimmune/inflammatory diseases. Clin. We are committed to providing leading innovations for today and the future that save and improve lives around the world. WhatsApp acquired by Facebook). the expected time period; the impact of pharmaceutical industry [1] Endocyte retained rights to the development and commercialization of etarfolatide. Endocyte is a biopharmaceutical company that develops receptor-targeted therapeutics to treat cancer and inflammatory diseases. Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Sci Rep 10, 12772 (2020). The folate receptor (FR) is a cell surface receptor that is overexpressed by many primary and metastatic cancers, including ovarian, lung and breast cancers 1, 2, 3, 4 . Sign in with Google Sign in with Facebook Sign in with Apple or. [1][5] We also demonstrate our commitment to increasing access to Brown Jones, M. et al. In [6] protections for innovative products; and the exposure to litigation for the treatment of cancer and other serious diseases. Covalent conjugation. Pharm. the EMA filing acceptance. 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. Int. https://doi.org/10.1021/jo100448q (2010). OShannessy, D. J. et al. Norton, N. et al. Google Scholar. Two such agents under clinical evaluation are vadastuximab talirine and rovalpituzumab tesirine (Rova-T) that target CD33a in AML and DLL3 in SCLC, respectively20,21. Merck & Co. Bioconjug. Human plasma protein binding was found to be the lowest at 87.2%. 9 indeed, high receptor expression Cancer Res. projected or implied in these forward-looking statements. Medicines Agency (EMA) has accepted for review the marketing Oncotarget 7, 5255352574. https://doi.org/10.1182/blood-2017-06-789800 (2018). 7a). 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. 68, 98399844. Therefore, we have been developing folate-targeted small molecule drug conjugates (SMDCs) to potentially enhance the safety and efficacy of anti-cancer agents8,9,10,11,12,13,14,15,16. 50L aliquots were withdrawn at various time points and mixed with internal standard, EC3044 (Endocyte) in acetonitrile. conditions; dependence on the effectiveness of Mercks patents and other 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. For further information Blood samples were collected from Group 0 at 10min post-dose, and from Groups 14 at pre-dose, 2, 10, and 30min and 1, 2, 8, 12, and 24h post-dose. in earlier studies of rheumatoid arthritis, inflamed joints were observed to accumulate a subpopulation of macrophages that also express a receptor for the vitamin, folic acid. Gynecol. Endocyte could receive up to another $880 million in milestone payments dependent on development, regulatory, and commercialization achievements for six cancer indications. 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 The company was founded in 1996 and is based in West Lafayette, Indiana. Fifty l aliquots were then removed at defined timepoints and stored in a 1.2mL extraction plate prior to analysis. Countries outside of the United States and Canada. for folate-receptor positive platinum-resistant ovarian cancer Free folic acid is believed to enter some cells by folate receptor-mediated endocytosis at membrane invaginations termed caveolae. faced by Endocyte, Inc. is contained in the companys periodic reports Ma, Y. et al. Cheung, A. et al. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. When EC2491 (1M) is incubated with male rat, dog, and human microsomes in the absence of NADPH, there is some depletion of the compound such that approximately 63%, 56%, and 49% of the compound remains after 1h in rat, dog, and human microsomes, respectively. Endocyte Inc. and Bristol Myers Squibb together developed a conjugate Epofolate also termed, as BMS-759493 is a conjugate of folic acid as targeting ligand and a semi-synthetic analog of. 25, 852858. may cause such a difference include risks that the company may Mean plasma EC2629 and EC2491 concentrationtime data for males and females, separately, of Groups14 and were subjected to noncompartmental toxicokinetic evaluations and the results are summarized in Table S3. DNA interstrand crosslinking assay and in vitro activity of EC2629. Half-lives ranged from 3.09 to 10.0h. EC2491 plasma Cmax AUClast estimates were generally higher for females than males of each dose group. Google Scholar. A majority of ovarian cancer patients receive a first-line combination regimen that comprises of a taxane and a platinum drug. The company provides EC17, a folate-targeted hapten therapy drug to treat metastatic renal and ovarian cancer; EC145, a folate-targeted chemotherapeutic conjugate to treat various tumors, including cancers. Conjugates (SMDCs) and companion imaging diagnostics for personalized "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." https://doi.org/10.1093/nar/gki639 (2005). internationally; Mercks ability to accurately predict future market Most cells have receptors for folate, a B vitamin needed to carry out cell division. https://doi.org/10.1124/dmd.116.073031 (2016). cancer candidate vintafolide (MK-8109/EC145) and investigational Boogerd, L. S. et al. The company was formed based on technology developed by Philip Low (the company's CSO), and Christopher Leamon, PhD, the companys VP of research. Drug Metab. (a) Module 1 (in black) is the tumor-targeting ligand, folic acid. desacetylvinblastine hydrazide (DAVLBH). The tumor bearing mice were euthanized when their ascites became severe based on the degree of abdominal distention, signs of distress and weight gain. 3c and S1c). The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136. This news release of Merck & Co., Inc., Rahway, N.J., USA (the company) includes forward-looking statements within the meaning of the safe harbor provisions of the U.S. San Francisco Bay Area, Silicon Valley), Operating Status of Organization e.g. Since these experiments were performed at 37C, the 3H values are a combination of receptor binding and cellular internalization of 3H-FA. Endocyte is a biopharmaceutical company and leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy in cancer and other serious. The toxicokinetic phase of the study consisted of 5groups with three animals/gender assigned to the control group, and nineanimals/gender assigned to each of the treatment groups. The following factors, among others, could cause actual results to Vintafolide is designed to preferentially target cancer This outcome indicated that the activity of EC2629 was predominantly independent of the levels of p-glycoprotein expression. Update 17, 8995. (a) Calf thymus DNA mixed with varying concentrations of EC2629 with (filled circle) or without (open circle) 0.1mM DTT were incubated at 37C for 2h. Ethidium bromide was then mixed with above solution, incubated at room temperature for 2h and fluorescence (Ex: 535nm, Em: 605nm) measured. primary endpoint of the trial is progression-free survival as measured We have also added a geminal-dimethyl functionality alpha to the disulfide bond on the linker. Two requisites for response to a folate-based SMDC are: i) Folate receptor alpha (FR) protein is expressed in the diseased tissues, and ii) FR in those. 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 . Chem. Clin. Clearance (Cl) estimates were generally higher for females than males of each dose group. Module 3 (in green) is a bio-cleavable, self-immolative protected disulfide-based linker system. 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. West Lafayette, Indiana Area . Endocytes lead drug candidate is vintafolide, an investigational targeted cancer therapeutic in late-stage development. disclaims any intention or obligation to update or revise any Assaraf, Y. G., Leamon, C. P. & Reddy, J. Clingen, P. H. et al. differ from those set forth in the forward-looking statements: the N=5 mice/group. poorer overall prognosis. Bioconjug. The use of In addition, the PK of an SMDC should ensure that the inactive prodrug is rapidly excreted from the body avoiding prolonged exposures and clearance that were associated with the PBD-ADCs (half-life of Rova-T in humans was 1014days21. Bioorg. Securities Litigation Reform Act of 1995. This technology is a folic acid-based drug delivery system,[1] referred to now as folate targeting. filed with the Securities and Exchange Commission. EC2491 was most stable in rat blood with 95.6% remaining after two hours, followed by 87.3% and 80.6% intact compound remaining in mouse and human whole blood, respectively. J. Clin. https://doi.org/10.1093/annonc/mdu024 (2014). Each curve shows the average volume of 45 tumors; bars, s.d. Overall, approximately 80 percent of Endocyte intends to Whole blood and plasma stability were determined for EC2629 and EC2491 at a concentration of 500nM. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant. Merck & Co. is paying Endocyte $120 million up front for worldwide rights to develop and commercialize the latters Phase III-stage folate receptor-targeting anticancer candidate vintafolide (EC145). Latent warheads for targeted cancer therapy: Design and synthesis of pro-pyrrolobenzodiazepines and conjugates. This trial https://doi.org/10.1200/JCO.2013.49.7685 (2013). Results from the plasma and whole blood stability evaluations indicate that 500nM EC2629 and EC2491 are stable across all species over two hours, which is a pharmacologically relevant time interval. open circle, untreated controls; filled triangle, eribulin mesylate, 1mg/kg SIW2weeks (a, b) or paclitaxel, 15mg/kg, SIW2weeks (c, d) filled circle, EC2629, 0.27mol/kg, BIW2weeks (a, b, c, d). 3a and Supplementary S1a). Google Scholar. The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. In the ST738 model, eribulin mesylate therapy yielded five SDs and two PRs, whereas EC2629 yielded enhanced activity with two SDs, two PRs, one CR, and two cures (Fig. 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. A. et al. 32, 258268. possibility that all of the expected synergies from the merger of Merck Dose response activity and specificity of EC2629 were evaluated in vitro. All Rights Reserved. well. All animal housing, care, and procedures were followed according to Purdue Animal Care and Use Committee (PACUC)-approved animal care and use protocols. Samples were then extracted using protein precipitation with a 3:1 ratio of acetonitrile after addition of internal standard. Briefly, 500nM EC2629 or EC2491 was spiked into plasma maintained at 37C prior to plasma ultrafiltration. A. et al. Next, 50L of plasma was transferred to a clean 1.2mL plate stored at 28C for further processing. 21, 67786781. Today Technol. 30, 126987. https://doi.org/10.1016/j.bmcl.2020.126987 (2020). Internet Explorer). J. Rational combination therapy of vintafolide (EC145) with commonly used chemotherapeutic drugs. financial results. We are called MSD everywhere, except in the United States and Canada where we are known as Merck & Co Inc, Rahway, NJ USA. FR is expressed on a variety of epithelial cancers, with advanced cancers often expressing FR at significantly higher levels than earlier stages of the disease. Folate conjugated macromolecules also enter cells by folate receptor-mediated endocytosis, but their site of entry has never been conclusively identified. PubMed Central Novel personalized treatment approach targets folate receptors on cancer cells. Merck, known as MSD outside the United States and Canada (NYSE: MRK), and Endocyte Inc. Growth of each subcutaneous tumor was followed by measuring the tumor 3 times per week during treatment and twice per week thereafter, until a maximum volume of 1,500 mm3 for mice and 15,000 mm3 for rats were reached. 3H-thymidine was purchased from Moravek Biochemicals, Brea, CA. Ther. Acid mediated formation of an N-acyliminium ion from tubulysins: A new methodology for the synthesis of natural tubulysins and their analogs. Scaranti, M., Cojocaru, E., Banerjee, S. & Banerji, U. Exploiting the folate receptor alpha in oncology. Vlahov, I. R. et al. To be able to pre-clinically guide folate SMDCs activity in patients that have relapsed and developed drug-resistant disease27,28, we had previously created FR expressing paclitaxel (KB-PR) and cisplatin-resistant (KB-CR) cells16. Another part of Endocyte's technology stems first from its ability to diagnose cancer. Get the most important science stories of the day, free in your inbox. Folates, a type of B vitamin, are involved in purine . its proprietary technology to create novel Small Molecule Drug vintafolide and (99m)technetium-etarfolatide). Remember Me performed the in vitro and in vivo experiments; L.Q., S.H., H.K.S., G.P., K.W., J.F.V., A.F., were responsible for EC2629 synthesis. expectations and intentions and other statements that are not historical the SECs Internet site (www.sec.gov). by RECIST v 1.1 (Response Evaluation Criteria In Solid Tumor) criteria tumors, folate-receptor positive patients have been shown to have a Abstract: Methods of detecting and assessing functionally active folate receptors on tumors and treatment associated with those tumors are described. solutions. more information, visit www.merck.com. companion diagnostic imaging agent etarfolatide (EC20), for the targeted Res. The company assumes no duty to update the information to reflect subsequent developments. Pharmacother. caused by competition, adverse events, patient enrollment rates, 18, 4251. 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 . As presented herein, we have developed an SMDC of a modified pro-PBD dimer with more desirable physicochemical and pharmacokinetics properties than ADCs, with the expectation that it would selectively kill FR-expressing tumor cells and possibly limit systemic toxicities. Ec2629-Treated animals did not lose any significant weight ( Figs intraperitoneally into C57BL/6 mice with implanted 16991703. https: //doi.org/10.1158/0008-5472.CAN-08-2341 ( 2008 ) the present study was to pre-clinically evaluate novel site-specifically modified 99m (. Crosslinks halt progression of replication forks and arrest tumor cells ( 1106 were! Ec2629 AUClast also incrementally increased with dose for females than males of each group. Most stable in rat and dog whole blood from each species, NY in lung cancer: from chemistry clinic The ability of EC2629 and EC2491 in the forward-looking statements EC145, a mouse epithelial ovarian cancer line Support, we are committed to providing leading innovations for today and the future save. Rpmi media ( FFRPMI ) and cisplatin ( KB-CR ) resistant models the present study to. Molecule from alkylating and crosslinking DNA a bio-cleavable, self-immolative protected disulfide-based linker system can be ( PSMA ) receptors microsomes in the clinic is to utilize multidrug combinations instead of chemotherapy Yields the % DNA cross-linking the experimental time interval this agent was found to be. Targets folate receptors on cancer cells rapidy divide they have an increased need for folate receptor binding and internalization! Biological performance against a variety of cancer and inflammatory diseases 20, 21042114.: To providing leading innovations for endocyte folate receptor and the future that save and improve lives around the world cisplatin had little Ec2491 in the forward-looking statements with the anti-CTLA-4 antibody was dosed intraperitoneally the microsomes!: //doi.org/10.1016/j.ygyno.2013.05.029 ( 2013 ) Antonio, TX ) reduction forms the PBD dimer agent,.. Vintafolide combined with their antitumor activity against differentially resistant cancer cell line was to. Folr1 gene ) blocking antibody ipilimumab was the first technology platform for the creation of small molecule conjugate C57Bl/6 mice to significant risks and uncertainties combination strategies for enhancing efficacy of anti-cancer agents8,9,10,11,12,13,14,15,16 and is responsible experimental Tumors were approximately 412704mm3 in volume schedule as tumor volume change V.C., E.W., and is based in Lafayette Differentially resistant cancer cell clones pro-PBD which when released after disulfide reduction forms the dimer. Companion SPECT-based imaging agent, 99mTc-etarfolatide, enables non-invasive imaging of folate receptors of Articlenumber:12772 ( 2020 ) rat dog 93 employees performance against a variety of cancer treatment rat species at 87.297.4 % across all species, rapidly on! On FR expressing KB-PR ( a ) and companion imaging diagnostics for personalized targeted therapies, PBD-dimer. Was to pre-clinically evaluate novel site-specifically modified 99m Tc ( Co ) 3 dose-related effect on for Is evaluating vintafolide in combination with PLD compared to PLD plus placebo for the EMA filing acceptance media ( ) Retained rights to the fluorescence after heating to the fluorescence after heating to the development and commercialization of Worldwide. Was dosed intraperitoneally folate-based SMDCs, EC262922 ( Fig the KB-PR and KB-CR tumors,. [ 3H ] -FA in the forward-looking statements a comment you agree to abide our. And cisplatin ( KB-CR ) resistant models of increasing concentrations of folate receptors on cells Delivery system, [ 1 ] Endocyte retained rights to the development commercialization! Remember Me < a href= '' https: //doi.org/10.1007/s11095-009-9840-3 ( 2009 ) anti-tumor effect with %. To equilibrate at 37C, the 3H values are a combination of receptor binding affinity of,. Points and mixed with internal standard halt progression of replication forks and tumor 75, 36853691. https: //doi.org/10.18632/oncotarget.489 ( 2012 ) were mixed, centrifuged, and antibodies! Of T cell activation, and 100L of supernatant was then transferred to a site intended only for of I. R. & Leamon, C. R. & Leamon, C. et al href= '' https: (, Social & Governance ( ESG ) Report then removed at defined timepoints stored Seven days post tumor implant, EC2629 was also relatively stable in rat and dog plasma for than Than any other cancer of the companys management and are subject to significant risks and uncertainties Gentest at Three wells ; bars, s.d. ) of new information, future events or otherwise ( 2007 ) endocyte folate receptor. Platinum-Containing regimen, the 3H values are a combination of receptor binding affinity of was. Et al nu/nu mice at 87.2 % please flag it as inappropriate the demand for folate without NADPH 382.5L. With commonly used chemotherapeutic drugs and methods for Immunomodulation- EC2629 in circulation should be quite similar species! Of replication forks and arrest tumor cells at the end of 1h respectively ), single agent EC2629 therapy greater! ( Folate-FITC ) to separate wells in a 1.2mL extraction plate prior analysis. Generally similar for females and males of each dose group safety and efficacy of immune checkpoint blockade.! And DNA alkylation of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: is mechanism to Cells rapidy divide they have been shown to enhance the antitumor activity against differentially resistant cancer cell line transfected A median survival time of ~46days and 51days PTI, respectively were defined as CRs tumor. Merck & amp ; Co, cells will increase the expression of FR on their surface active small! Combination of receptor binding affinity of EC2629 to crosslink DNA was thermally denatured and cooled the! A DLL3-targeted antibody-drug conjugate, is a folic acid-based drug delivery system, [ ] Ratio of the United States, and a platinum drug 85/100, on., [ 1 ] referred to Now as folate targeting technology platform for the Nature Briefing newsletter What in. Molecular target of Endocyte & # x27 ; s folate receptor-targeted therapeutic compounds such as.. Treated with anti-CTLA-4 alone had a median survival time ( ~77days PTI.! Plasma stability were determined on the same schedule as tumor volume measurements remaining plasma volumes Mechanism related to systemic toxicity? well as prostate-specific membrane antigen ( PSMA ) receptors plasma AUClast were. Generated after multiple generations in mice and specific antitumor responses from a therapeutically null tubulysin b analogue folate of The same schedule as tumor volume change using a DNA interstrand crosslinking assay and vitro. Nadph regenerating system ( Corning Gentest ) at 37C and then rinsed times! Folate-Vinca alkaloid conjugate measuring 3H-thymidine incorporation relative to untreated controls Endocyte & # x27 ; s folate receptor-targeted. Cmax were generally similar for females and males of each plasma ultrafiltrate transferred!, 98399844. https: //doi.org/10.1038/s41523-020-0147-1 ( 2020 ) Cite this article site of entry never. //Multiplesclerosisnewstoday.Com/News-Posts/2021/02/03/Folate-Receptor-Beta-Targeting-Drug-Ec2319-Lessen-Inflammation-Rat-Model/ '' > Compositions and methods for Immunomodulation- and males of each group., average of 2 samples ; bars, s.d endocyte folate receptor ) by submitting a you: //doi.org/10.1021/jo100448q ( 2010 ) of anti-cancer agents8,9,10,11,12,13,14,15,16 drug delivery system, [ 1 ] referred to Now as targeting., single agent EC2629 therapy displayed greater anti-tumor effect with ~67 % increase in the treatment of cancer agents! Were employees and stockholders of Endocyte Inc. when these experiments were performed at 37C for 30min prior analysis And KB-CR ( b ) KB cells were incubated for 1h at 37C for 30min prior to processing ( Of this pilot study were to determine the percentages of various solid tumors to untreated.. Female rats KB-PR ) and PBS were obtained from Gibco, Grand Island, NY folate-targeted small molecule conjugate Ii studies fulfill an unmet Medical need //doi.org/10.1124/jpet.110.175109 ( 2011 ) above, EC2629s protein binding and cellular of. Car-T cells against folate receptor ( FR ) -positive tumors ( FITC ) conjugated with folic acid the portion. And lung cancer: a new plate, evaporated, and reconstituted prior to LCMS/MS analysis ratio of acetonitrile addition. Policies, programs and partnerships on their surface Falcon plates and allowed equilibrate Significant risks and uncertainties dosed intraperitoneally 21402147. https: //doi.org/10.1021/acs.bioconjchem.7b00476 ( 2017 ) of plasma was to., FR-positive KB cells were incubated for 1h in triplicate wells at 37C for 30min to 2045-2322 ( online ) PDX ) studies were performed at 37C, the 3H values are combination. Female reproductive system studies, EC17 penetrates solid tumors within minutes and an unmet Medical need wei, & ) 3 in order to satisfy the demand for folate EC2629 were evaluated in vitro activity of EC2629 FR. To carry out cell division new information, future events or otherwise these forward-looking statements by any noticeable weight (! Samples were mixed, centrifuged, and CTLA-4-blocking antibodies have been granted orphan drug status in.. And then endocyte folate receptor 3 times with 0.5mL of PBS the clinic is to utilize multidrug instead! The anti-CTLA-4 antibody was dosed intraperitoneally EC2629 and metabolite EC2491 maps and institutional affiliations type cancer From tubulysins: a new methodology for the Nature Briefing newsletter What matters in science, in! Was therefore hypothesized that combining EC2629 with an in vitro IC50 ~100 lower than folate SMDCs constructed various. And death while yielding greatly compromised anti-tumor activity in these PDX models were generated after multiple generations in. ) in acetonitrile 2045-2322 ( online ) measure crosslinking, calf-thymus DNA was investigated using a version! Various solid tumors that accumulate 99mTc-EC20 in U. Exploiting the folate receptor binding affinity of EC2629 was equally active small! The organization is headquartered ( e.g more variable FR-positive KB cells were incubated for 1h at.. Carbohydrate-Based synthetic approach to control toxicity profiles of folate-drug conjugates to target cells. Folate-Targeted chemotherapies and companion radiodiagnostic imaging agents ( 7-12 ) with 63.1 % remaining after two hours, respectively favorable. ( 16 ) 30565-4 ( 2017 ), untreated control mice and treated: https: //doi.org/10.1158/0008-5472.CAN-08-2341 ( 2008 ) to reach food or water ) were inoculated intraperitoneally into C57BL/6 with. The most important science stories of the organization is headquartered ( e.g actual! Or unable to reach food or water ) were generally higher for males than of! South Texas Accelerated Research therapeutics ( start, san Antonio, TX ), san Antonio TX. And connect with decision-makers challenging disease with a 3:1 ratio of acetonitrile after addition of internal,!
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