Christopher P Leamon

Endocyte, ウェストラファイエット, Indiana, United States

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Publications (95)551.48 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):4393-4393. DOI:10.1158/1538-7445.AM2015-4393 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4488-4488. DOI:10.1158/1538-7445.AM2015-4488 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4495-4495. DOI:10.1158/1538-7445.AM2015-4495 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):5359-5359. DOI:10.1158/1538-7445.AM2015-5359 · 9.33 Impact Factor
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    ABSTRACT: Folate receptor (FR)-β has been identified as a promising target for anti-macrophage and anti-inflammatory therapies. In the present study we investigated EC0565, a folic acid derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Due to its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture, and FR-binding specificity. Using FR-expressing macrophages, the effect of EC0565 on mTOR signaling and cellular proliferation was studied. EC0565's pharmacokinetics, metabolism, and bioavailability were studied in normal rats. EC0565's in-vivo activity was assessed in rats with adjuvant arthritis, a "macrophage-rich" model with close resemblance to rheumatoid arthritis.EC0565 forms micellar aggregates in physiological buffers and demonstrates good water solubility as well as strong multivalent FR-binding capacity. EC0565 inhibited mTOR signaling in rat macrophages at nanomolar concentrations and induced G0/G1 cell cycle arrest in serum-starved RAW264.7 cells. Subcutaneously administered EC0565 in rats displayed good bioavailability and a relatively long half-life (~12 h). When given at 250 nmol/kg, EC0565 selectively inhibited proliferating cell nuclear antigen expression in thioglycollate-stimulated rat peritoneal cells. With limited dosing regimens, EC0565's anti-arthritic activity was found superior to that of etanercept, everolimus, and a non-targeted everolimus analog. EC0565's in-vivo activity was also comparable to that of a folate-targeted aminopterin. Folate-targeted mTOR inhibition may be an effective way of suppressing activated macrophages in sites of inflammation, especially in nutrient deprived conditions such as in the arthritic joints. Further investigation and improvement upon EC0565's physical and biochemical properties are warranted.
    Molecular Medicine 07/2015; DOI:10.2119/molmed.2015.00040 · 4.51 Impact Factor
  • Ignace Vergote · Christopher P Leamon ·
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    ABSTRACT: Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early-stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents.
    07/2015; 7(4). DOI:10.1177/1758834015584763
  • Yehuda G. Assaraf · Christopher P. Leamon · Joseph A Reddy ·
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    ABSTRACT: Conventional cancer treatment modalities have several limitations including lack of sufficient efficacy, serious untoward toxicity, as well as innate and acquired drug resistance. In contrast, targeted imaging agents can identify patients with receptors overexpressed on the surface of cancer cells, thus allowing appropriate selection of patients for personalized treatment with a desirable targeted therapeutic. The folate receptor (FR) has been identified as a new molecularly targeted entity, which is highly overexpressed on the surface of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain, endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, head and neck, breast, and non–small cell lung cancer. Folic acid conjugation is a novel approach for targeting FR-expressing tissues for personalized treatment. With the development of FRα-targeted therapies comes a concomitant prerequisite for reliable methods for the quantification of FRα tissue expression. Therefore, attaching a radioactive probe to folic acid to target diseased tissue has become a novel and powerful imaging technique. Currently available diagnostic tools frequently require invasive surgical biopsy. In contrast, the noninvasive single-photon emission computed tomography-based companion imaging agent, 99mTc-etarfolatide (99mTc-EC20), is in development for use as a companion diagnostic with the FRα-targeted folate conjugate, vintafolide (EC145), to identify patients whose tumors express FRα. Vintafolide is a folic acid conjugate of Vinca alkaloid (desacetylvinblastine hydrazide) that targets FRα-expressing tumors, thereby disrupting microtubule polymerization. 99mTc-etarfolatide is taken up by FR-positive tumors and allows for noninvasive, whole-body monitoring of FRα expression status throughout treatment. The combination of vintafolide plus etarfolatide has been evaluated in three Phase 2 studies for the treatment of various solid tumors, including ovarian, endometrial, peritoneal, and platinum-resistant ovarian cancer, as well as lung cancer. Patients with FR-positive tumors, as identified by etarfolatide uptake, have had better clinical outcomes than patients with FR-negative tumors, indicating the potential of etarfolatide as a companion biomarker for predicting vintafolide response. Targeted therapies combined with a reliable companion diagnostic test represent a novel approach towards efficient personalized medicine for malignant and nonmalignant disorders. Furthermore, the recent availability of the crystal structures of FRα and FRβ in complex with folates and antifolates forms a realistic basis for the rational design and implementation of novel FR-targeted drugs for the treatment of cancer and inflammatory disorders.
    Drug Resistance Updates 10/2014; 17(4-6). DOI:10.1016/j.drup.2014.10.002 · 9.12 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):4462-4462. DOI:10.1158/1538-7445.AM2014-4462 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):832-832. DOI:10.1158/1538-7445.AM2014-832 · 9.33 Impact Factor
  • Nikki Parker · Christina Cherian · Larry Matherly · Christopher P. Leamon ·

    Cancer Research 10/2014; 74(19 Supplement):4591-4591. DOI:10.1158/1538-7445.AM2014-4591 · 9.33 Impact Factor
  • CP Leamon · JA Reddy · M. Nelson · A. Bloomfield · R. Dorton · M. Vetzel ·

    Cancer Research 03/2014; 73(24 Supplement):P2-16-24-P2-16-24. DOI:10.1158/0008-5472.SABCS13-P2-16-24 · 9.33 Impact Factor
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    ABSTRACT: Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.
    Bioconjugate Chemistry 02/2014; 25(3). DOI:10.1021/bc400441s · 4.51 Impact Factor
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    ABSTRACT: Objective-To determine expression of folate receptors (FRs) and folate uptake in multicentric lymphomas in dogs. Sample-10 dogs with histopathologically confirmed multicentric lymphoma and 20 archival lymph node biopsy specimens from dogs with multicentric lymphoma. Procedures-Multicentric lymphomas in 10 dogs were prospectively evaluated for FR expression by use of immunohistochemical analysis and for in vivo folate uptake by use of nuclear scintigraphy. Dogs with FR-expressing tumors were eligible for FR-targeted chemotherapy. Twenty archival lymphoma biopsy specimens were also evaluated with immunohistochemical analysis. Results-FRs were not detected with immunohistochemical analysis in lymph node samples obtained from the 10 dogs or in archival biopsy specimens. However, nuclear scintigraphy revealed uptake of radioactive tracer in 6 of 10 dogs. Five of these 6 dogs were treated with an FR-targeted chemotherapeutic agent; results of treatment were complete remission in 1 dog, stable disease in 2 dogs, and progressive disease in 2 dogs. Treatment-related toxicoses generally were mild. Conclusions and Clinical Relevance-This study provided strong evidence for folate uptake in a substantial portion of multicentric lymphomas of dogs and indicated the antitumor activity of FR-targeted chemotherapeutics for these cancers. Use of FR-targeted chemotherapeutics may be promising for the treatment of FR-expressing multicentric lymphomas in dogs. Further studies are needed to determine reasons for lack of immunoreactivity to currently identified anti-FR antibodies and to develop improved methods for detecting FRs in lymphomas of dogs.
    American Journal of Veterinary Research 02/2014; 75(2):187-94. DOI:10.2460/ajvr.75.2.187 · 1.34 Impact Factor
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    ABSTRACT: When evaluated in ovarian and other cancer patients, vintafolide (EC145), a potent folate-targeted vinca alkaloid conjugate, displayed a toxicity profile that appeared to be non-overlapping with many standard of care cancer therapeutics. It was therefore hypothesized that combining vintafolide with certain approved anticancer drugs may afford greater therapeutic efficacy compared to single-agent therapy. To explore this concept, vintafolide was evaluated in combination with pegylated liposomal doxorubicin (PLD; DOXIL®), cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, and irinotecan against folate-receptor (FR)-positive models. FR-expressing KB, M109, IGROV, and L1210 cells were first exposed to graded concentrations of vintafolide, either alone or in combination with doxorubicin (active ingredient in PLD), and isobologram plots and combination index values generated. The vintafolide combinations were also studied in mice bearing various FR-expressing tumors. Vintafolide displayed strong synergistic activity against KB cells when combined with doxorubicin, and no less-than-additive effects resulted when tested against M109, IGROV, and L1210 cells. In contrast, when either desacetylvinblastine hydrazide (DAVLBH; the vinca alkaloid moiety in vintafolide) or vindesine (the vinca alkaloid most structurally similar to DAVLBH) were tested in combination with doxorubicin, less-than-additive antitumor effects were observed. In vivo, all vintafolide drug combinations produced far greater antitumor effect (complete responses and cures) compared to the single agents alone, without significant increase in overall toxicity. Importantly, these benefits were not observed with combinations of PLD and DAVLBH or vindesine. Based on these encouraging preclinical results, clinical studies to evaluate vintafolide drug combination therapies are now underway.
    Clinical Cancer Research 01/2014; 20(8). DOI:10.1158/1078-0432.CCR-13-2423 · 8.72 Impact Factor
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    ABSTRACT: EC0746 is a rationally designed anti-inflammatory drug conjugate consisting of a modified folic acid-based ligand linked to a γ-hydrazide analog of aminopterin. In this report, EC0746's effectiveness was evaluated against experimental retinal S-antigen (PDSAg) induced autoimmune uveitis (EAU) and myelin-basic-protein induced autoimmune encephalomyelitis (EAE). In both models, functional FR-β was detected on activated macrophages in local (retinal or central-nervous-system, respectively) and systemic (peritoneal cavity) sites of inflammation. In myelin-rich regions of EAE rats, an increased uptake of (99m)Tc-EC20 (etarfolatide; a FR-specific radioimaging agent) was also observed. EC0746 treatment at disease onset suppressed the clinical severity of both EAU and EAE, and it strongly attenuated progressive histopathological changes in the affected organs. In all parameters assessed, EC0746 activity was completely blocked by a benign folate competitor, suggesting that these therapeutic outcomes were specifically FR-β mediated. EC0746 may emerge as a useful macrophage-modulating agent for treating inflammatory episodes of organ-specific autoimmunity.
    Clinical Immunology 10/2013; 150(1):64-77. DOI:10.1016/j.clim.2013.10.010 · 3.67 Impact Factor
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    ABSTRACT: Human pituitary adenomas express folate receptors (FR); therefore, we hypothesized that parathyroid (PT) tumors also might express FR, whereas normal human thyroids might not. The purpose of our study was to characterize the functionality of FRs on human PT tumors, with the goal of developing an imaging tool that would concentrate in PT more than in the thyroid. Human PTs and thyroids were evaluated for FR expression by immunohistochemistry. Expression of genes for FRα and FRβ was measured with the Illumina Human HT-12 Expression Bead Chips and verified by quantitative reverse-transcription polymerase chain reaction. Folate incorporation by PT cells versus normal thyroid cells was determined by incubation with (99m)Technetium ((99m)Tc)(CO)3-folate and (99m)Tc-Etarfolatide, and uptake was determined by gamma counting. Specific targeting of FRs was demonstrated by blocking with cold folate. A549 cells and Jurkat cells served as FR-negative controls, and KB cells and HeLa cells were FR-positive controls. On immunohistochemistry and Western blotting, human PT cells expressed FRs, whereas human thyroid cells did not. The FRα gene was expressed in all PTs analyzed, and the FRβ gene was expressed by most. Uptake of (99m)Tc(CO)3-folate was increased in PT cells versus thyroid cells. There was dose-dependent uptake of (99m)Tc-etarfolatide, and uptake was inhibited by preincubation with cold folate, confirming FR-mediated binding. This is the first report of the expression and functionality of FRs on human PT cells. These findings suggest that (99m)Tc-folate holds potential for localization of PT tumors preoperatively and their treatment.
    Surgery 10/2013; 154(6). DOI:10.1016/j.surg.2013.06.045 · 3.38 Impact Factor
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    ABSTRACT: 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. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
    Journal of Clinical Oncology 10/2013; 31(35). DOI:10.1200/JCO.2013.49.7685 · 18.43 Impact Factor
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    Christopher P Leamon · Chandra D Lovejoy · Binh Nguyen ·
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    ABSTRACT: Ovarian cancer (OC) has the highest mortality rate of any gynecologic cancer, and patients generally have a poor prognosis due to high chemotherapy resistance and late stage disease diagnosis. Platinum-resistant OC can be treated with cytotoxic chemotherapy such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine, but many patients eventually relapse upon treatment. Fortunately, there are currently a number of targeted therapies in development for these patients who have shown promising results in recent clinical trials. These treatments often target the vascular endothelial growth factor pathway (eg, bevacizumab and aflibercept), DNA repair mechanisms (eg, iniparib and olaparib), or they are directed against folate related pathways (eg, pemetrexed, farletuzumab, and vintafolide). As many targeted therapies are only effective in a subset of patients, there is an increasing need for the identification of response predictive biomarkers. Selecting the right patients through biomarker screening will help tailor therapy to patients and decrease superfluous treatment to those who are biomarker negative; this approach should lead to improved clinical results and decreased toxicities. In this review the current targeted therapies used for treating platinum-resistant OC are discussed. Furthermore, use of prognostic and response predictive biomarkers to define OC patient populations that may benefit from specific targeted therapies is also highlighted.
    Pharmacogenomics and Personalized Medicine 09/2013; 6(1):113-125. DOI:10.2147/PGPM.S24943
  • Josefine Reber · Stephanie Haller · Christopher P Leamon · Cristina Mueller ·
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    ABSTRACT: Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor (FR) has been identified specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect to reduce undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate, 177Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of 177Lu-EC0800 and PMX on the viability of FR positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor bearing mice were treated with 177Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of 177Lu-EC0800 with PMXther resulted in a 2-4-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of 177Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was demonstrated by determination of plasma parameters and quantitative SPECT using 99mTc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy, and prevented undesired radio-nephrotoxicity.
    Molecular Cancer Therapeutics 09/2013; 12(11). DOI:10.1158/1535-7163.MCT-13-0422-T · 5.68 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):4499-4499. DOI:10.1158/1538-7445.AM2013-4499 · 9.33 Impact Factor

Publication Stats

4k Citations
551.48 Total Impact Points


  • 2008-2014
    • Endocyte
      ウェストラファイエット, Indiana, United States
  • 2012
    • University of California, Santa Barbara
      • Department of Molecular, Cellular, and Developmental Biology
      Santa Barbara, CA, United States
  • 2007
    • ImmunoGen, Inc.
      Волтам, Massachusetts, United States
  • 1991-2005
    • Purdue University
      • Department of Chemistry
      ウェストラファイエット, Indiana, United States