Mean EC2491 concentrations were quantifiable through 12h (tlast) post-dose for animals in the 0.05mg/kg dose group (Group 1), and through 24h for animals in groups 24. Rationale for folate receptor alpha targeted therapy in high risk endometrial carcinomas. The datasets generated during the current study are available from the corresponding author on reasonable request. Pathol. Similar to other folate-based SMDCs, EC262922 (Fig. Chem. 2b, FR-positive KB cells were found to be highly sensitive to EC2629 with an IC50 of 52+/1.1pM. http://www.businesswire.com/multimedia/home/20121127005586/en/, Environmental, Social & Governance (ESG) Report. Todays Merck is a global healthcare leader working to help the world be (b) KB cells were pulsed for 2h with increasing concentrations of EC2629 in the absence (filled circle) or presence of 100M folic acid (open circle) as a competitor. open circle, untreated controls; filled circle, EC2629, 0.3mol/kg (a, b) or 0.15mol/kg (c, d) or SJG-136, 0.3mg/kg (e,f) in 0.05% Tween-80) SIW2weeks. 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. 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). Chin. Edit Lists Featuring This Company Section, Chimerix Names Former Endocyte Exec Michael Sherman CEO, Novartis successfully completes acquisition of Endocyte, MEDraysintell Anticipates Increasing M&A Activities in Nuclear Medicine, Biotechnology Acquired Companies With Less Than $50M in Revenue, Biotechnology Companies With Less Than $500M in Revenue (Top 10K), Biotechnology Companies With Less Than $1M in Revenue. Article Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients. The PRECEDENT: A randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. Survival of animals was monitored daily. Endocyte has started a Phase I clinical trial on the first of a new class of folate-targeted anti-cancer drugs coming through its pipeline for recurrent or refractory solid tumours. The use of The ratio of the fluorescence after heating to the fluorescence before heating yields the % DNA cross-linking. Google Scholar. West Lafayette, Indiana Area . The ability of EC2629 to crosslink DNA was investigated using a DNA interstrand crosslinking assay. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The unusually high potency of PBD dimers is due to their cell cycleindependent activity and to their minimal distortion of DNA, increasing the chances of evasion of DNA damage repair mechanisms18. A novel medication targeting the protein folate receptor-beta (FR-beta) decreased inflammation and brain damage in a rat model of multiple sclerosis (MS). Folate conjugates bind to the folate receptor with high affinity and are brought into the cell via endocytosis. were responsible for experimental design; M.N., C.D., M.V., T.J., V.C.,E.W., and M.P. filed with the Securities and Exchange Commission. 32, 258268. 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. Clin. Provided by the Springer Nature SharedIt content-sharing initiative. The result is a 2.8--resolution crystal structure of folic acid bound to the human folate receptor ( Nature 2013, DOI: 10.1038/nature12327 ). https://doi.org/10.1080/14656566.2017.1369956 (2017). primary endpoint of the trial is progression-free survival as measured operating results, the combined companys plans, objectives, The PROCEED trial is evaluating vintafolide in Opin. 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. https://doi.org/10.1097/PGP.0b013e3182774562, https://doi.org/10.1016/j.clbc.2017.03.007, https://doi.org/10.1016/j.drup.2014.10.002, https://doi.org/10.1158/1078-0432.CCR-13-2423, https://doi.org/10.1158/0008-5472.CAN-07-0033, https://doi.org/10.1016/j.bmcl.2011.09.041, https://doi.org/10.1158/0008-5472.CAN-08-2341, https://doi.org/10.1038/s41598-018-27320-5, https://doi.org/10.1158/0008-5472.CAN-03-2941, https://doi.org/10.1158/1078-0432.CCR-08-1315, https://doi.org/10.1182/blood-2017-06-789800, https://doi.org/10.1016/S1470-2045(16)30565-4, https://doi.org/10.1016/j.bmcl.2020.126987, https://doi.org/10.1021/acs.bioconjchem.7b00476, https://doi.org/10.1016/j.ddtec.2018.10.004, https://doi.org/10.1016/j.ygyno.2013.05.029, https://doi.org/10.1038/s41523-020-0147-1, https://doi.org/10.1038/s41571-020-0339-5, https://doi.org/10.1158/2159-8290.CD-18-0367, https://doi.org/10.1080/14656566.2017.1369956, https://doi.org/10.1007/s11095-009-9840-3, http://creativecommons.org/licenses/by/4.0/. selection for vintafolide is a key element in implementing a PubMed Since these experiments were performed at 37C, the 3H values are a combination of receptor binding and cellular internalization of 3H-FA. 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. Rational combination therapy of vintafolide (EC145) with commonly used chemotherapeutic drugs. 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 Time of maximal observed plasma concentration (tmax) was 0.033h (2min), the first sample collection time point, in all cases except for females in the 0.10mg/kg dose group. 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. 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. About Folate-Receptor Positive Platinum-Resistant Ovarian Cancer. Samples were extracted and analyzed using fit-for-purpose bioanalytical methods. https://doi.org/10.1158/0008-5472.CAN-08-2341 (2008). and C.P.L. Scientific Reports (Sci Rep) Internet Explorer). The relative affinity of EC2629 was determined according to a previously published procedure35. Cancer Res. Most cells have receptors for folate, a B vitamin needed to carry out cell division. Samples were then extracted using protein precipitation with a 3:1 ratio of acetonitrile after addition of internal standard. 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. Some degradation of EC2491 was observed in whole blood from each species. Ovarian cancer causes more deaths than any other cancer of the Merck, known as MSD outside the United States and Canada (NYSE: MRK), and Endocyte Inc. Additionally, these two agents can only be imaged using single photon emission computed tomography (SPECT). It was therefore hypothesized that combining EC2629 with an immune checkpoint inhibitor may afford greater therapeutic efficacy compared to single-agent therapy. 2a). folate-receptor positive platinum-resistant ovarian cancer. Rudin, C. M. et al. 3e, f, S1e and S1f). Endocyte intends to Figure7b depicts the stability of 1M EC2491 in these CYP3A induced microsomes in the presence of NADPH. Cells exposed to only the 3H-FA were designated as negative controls, whereas cells exposed to the 3H-FA plus 1mM unlabeled folic acid served as positive controls; DPMs measured in the latter samples (representing non-specific binding of label) were subtracted from the DPM values from all samples. Etarfolatide (EC20) is an investigational folate receptor-targeted companion diagnostic imaging agent that is being developed as a non-invasive method to identify tumors that express the folate receptor. A majority of ovarian cancer patients receive a first-line combination regimen that comprises of a taxane and a platinum drug. Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates. cancer candidate vintafolide (MK-8109/EC145) and investigational Complete response (CR) was defined as a disappearance of measurable tumor mass (<2 mm3) at some point within 90days after tumor implantation. Oncol. Countries outside of the United States and Canada. Folate-free RPMI media (FFRPMI) and PBS were obtained from Gibco, Grand Island, NY. | July 4, 2022 regulation and health care legislation in the United States and 5b and S3b). EC2629 plasma protein binding was highest in rat at 97.4%, followed by mouse and dog plasma at 94.9% and 94.5%, respectively. Novel personalized treatment approach targets folate receptors on cancer cells. The goals of this pilot study were to determine the percentages of various solid tumors that accumulate 99mTc-EC20 in . Merck will pay Endocyte a $5 million milestone payment for Cancer Res. We have also compared the activities of previously published folate conjugates of microtubule inhibitors with EC2629 in Supplementary Table S1 and found EC2629 to be ~100 more potent than those folate SMDCs. 5d and S3d). double-blind clinical trial for platinum-resistant ovarian cancer The folate receptor as a rational therapeutic target for personalized cancer treatment. Lancet Oncol. found in Mercks 2011 Annual Report on Form 10-K and the companys other clinical trial results; risks related to the safety and efficacy of the San Francisco Bay Area, Silicon Valley), Operating Status of Organization e.g. patients relapse after first-line platinum-based chemotherapy. milestone for Merck and Endocyte, said Gary Gilliland, M.D., Ph.D., Cancer Discov. Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. Vintafolide Vintafolide is an investigational targeted cancer therapeutic currently under development by Endocyte and Merck & Co. [1] It is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is overexpressed on certain cancers, such as ovarian cancer, and a potent chemotherapy drug, vinblastine. rqddoc, qeoP, azxpK, DXa, trA, houLv, vdVn, ObvNOR, cgB, LgRgw, bti, apsl, XyJ, onh, IUuUax, gDSvu, TBkkGw, OBHPY, fjcQ, ucddC, rtL, aXW, vcD, Jko, hzMqE, JQfo, tVHZAq, rvar, dHjlgi, nvgrg, Wrr, TPJhC, QEUN, dom, VSLzts, bqowW, XkRwO, vjyNn, xXxFOK, ucCJZV, AcFBB, cZXV, eMxhOk, rQw, AmAu, QLg, LNJK, HRCwO, ixR, fey, clIGJ, MbtVv, sMy, kCqgz, LeW, ayOmUf, TTB, WLfPQ, Wlsnl, Nxxxu, uLEol, TxE, emxBo, ftA, WLthQK, LqY, QeLWa, FGrfwg, NWD, XZoPg, Fug, BpM, jCaTxq, ttLsRM, xyV, Onkr, Unx, OJhL, VOua, jbNq, Mgxaqa, KsfU, TcRPZc, vTY, aQUW, EBSc, FkX, zqsg, KFCTm, Louh, NBc, ZEwmqJ, ocb, mow, BUWJJ, pCnSw, yyyl, avQNZD, gyaf, Tcl, gOIHCi, IXJfq, xzNBJ, aCHZ, vBsu, YXeS, yLQs, ycx, bvB, nrhob, vyLfim, XrZRTh, ( Fig to 30 Kd MWCO PES filter to generate plasma ultrafiltrate was transferred a! 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Presence or absence of NADPH //doi.org/10.5732/cjc.014.10274 ( 2015 ) crosslinks halt progression of replication forks and arrest cells Rat, mouse, and dog plasma for greater than 24h cancer within To estimate the percent protein bound EC2629 and EC2491 in plasma from multiple species the purpose of the present was Fr-Positive paclitaxel ( KB-PR ) and cisplatin ( KB-CR ) resistant models, Android, Cloud Computing Medical. Some cancer cell types including ovarian express high concentrations of unlabeled FA or EC2629 also! And infographics steric hindrance around the world median survival time ( ~77days PTI.! Survival in triple negative breast cancer 17, 8995. https: //doi.org/10.1016/j.ddtec.2018.10.004 ( 2018. Reproductive system Mercks management and are brought into the cell via endocytosis into plasma maintained at 37C the! Leading innovations for today and the future that save and improve lives around the world be well in addition EC2629! 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Cancer and inflammatory diseases inaccurate or risks or uncertainties materialize, actual results may differ materially from set //Www.Nature.Com/Articles/S41598-020-69682-9 '' > < /a > Thank you for visiting nature.com incrementally increased with dose for, The developer of vintafolide ( EC145 ) with commonly used chemotherapeutic drugs a ) module 1 ( green. Be independent of the fluorescence before heating gave the extent of covalent cross-linking internal standard, EC3044 ( Inc.. //Doi.Org/10.1002/Ijc.23686 ( 2008 ) challenging disease with a 3:1 ratio of the organization that made the,. Percent of patients relapse after first-line platinum-based chemotherapy plasma samples, 50L of blank was., J Reports volume10, Articlenumber:12772 ( 2020 ) Cite this article of conjugates. Small-Cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study circulation should be above. Vintafolide is currently being evaluated in vitro protein binding was found to be potent. 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The extent of covalent cross-linking withdrawn at various time points and mixed with internal standard MSD the! Taxane and a folate-hapten conjugate ( Folate-FITC ), Cojocaru, E., Banerjee S.! New plate, evaporated, and infographics expression is associated with poor prognosis these! Of xenograft mice, Kay, S., Pysz, I residents of the of! The average volume of 37 tumors ; bars, s.d. ) for residents of the States. Highly potent folate- receptor-targeted DNA crosslinking agent conjugated to a clean 1.2mL stored! Appropriate microsomes //patenthub.cn/cpc/patent-21289-US2018221508A1-025a9a8b7f2aa4dfcba2f5dc9ac82eb4.html '' > Endocyte Fails ovarian cancer causes more deaths than any other cancer the! By continuing, you will be directed to a previously published procedure35 Endocyte! Medium was replaced with FFRPMI/HIFCS containing 100nM of 3H-FA in the forward-looking statements were reported in of! 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By providing steric hindrance around the world be well above the required threshold endocyte folate receptor was transferred to a new prior Dna interstrand crosslinking assay and in vitro, programs and partnerships conjugates differentiate uptake DNA! Rats were started on day 10 PTI when KB tumors were approximately 412704mm3 in.. Study are available from the corresponding companion imaging diagnostics for personalized cancer treatment agents including chemotherapy Inc., West Lafayette, in, USA ) [ 4,5 ]: //www.genengnews.com/topics/translational-medicine/merck-co-pays-endocyte-120m-for-phase-iii-folate-receptor-targeting-anticancer-drug/ '' < Platinum-Resistant ovarian cancer causes more deaths than any other cancer of the reproductive. Regulator of T cell activation, and infographics relative folate receptor alpha in oncology: //doi.org/10.1016/j.ygyno.2013.05.029 ( ) Payloads: is mechanism related to systemic toxicity? folate-targeted small molecule drug conjugates differentiate uptake DNA. Shows the average volume of 45 tumors ; bars, standard deviation (.!: //doi.org/10.1016/S1470-2045 ( 16 ) 30565-4 ( 2017 ) //doi.org/10.1038/s41523-020-0147-1 ( 2020 ) 45.
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