المؤلفون: O’Connor, Brian P, Grogan, Bryan M, James, Reice D, Ulrich, Michelle L, Berndt, Jason D, Lu, Hailing, Conerly, Melissa, Clarke, Astrid, Hamblett, Kevin J, Heiser, Ryan A

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.1155Test

المؤلفون: Pavel, Helena, Ajeawung, Norbert, Faure, Robert, Poirier, Donald, Kamnasaran, Deepak, Joshi, Harish, Lun, Xueqing, Zemp, Franz, Sun, Beichen, Stechishin, Owen, Luchman, Artee, Kelly, John J., Weiss, Samuel, Hamilton, Mark G., Cairncross, Gregory, Senger, Donna L., Bell, John, McFadden, Grant, Forsyth, Peter A., Tzeng, Stephany Y., Guerrero-Cazares, Hugo, Martinez, Elliott E., Young, Noah P., Sunshine, Joel C., Quinones-Hinojosa, Alfredo, Green, Jordan J., Lei, Liang, D'Amico, Randy, Sisti, Julia, Leung, Richard, Sonabend, Adam M., Guarnieri, Paolo, Rosenfeld, Steven S., Bruce, Jeffrey N., Canoll, Peter, Baichwal, Vijay R., Reeves, Leslie, Chad, Bradford L., Zavitz, Kenton H., Beelen, Andrew P., Mather, Gary G., Carlson, Robert O., Manton, Christa, Chandra, Joya, Keir, Stephen T., Reardon, David A., Saling, Julia R., Gray, Lloyd S., Bigner, Darell D., Friedman, Henry S., Zhang, Jiqing, Brun, Jan, Ogbomo, Henry, Wang, Zhigang, Stojdl, David J., Kong, Ling-Yuan, Hatiboglu, Mustafa A., Wei, Jun, Wang, Yongtao, McEnery, Kayla A., Fuller, Gregory N., Qiao, Wei, Davies, Michael A., Priebe, Waldemar, Heimberger, Amy B., Amendolara, Benjamin, Gil, Orlando, Ivkovic, Sanja, Bruce, Jeffrey, Rosenfeld, Steven, Finniss, Susan, Perlstein, Benny, Miller, Cathie, Okhrimenko, Hana, Kazimirsky, Gila, Cazacu, Simona, Lemke, Nancy, Brodie, Shlomit, Rempel, Sandra A., Rosenblum, Mark, Mikkelsen, Tom, Margel, Shlomo, Brodie, Chaya, Guvenc, Hacer, Demir, Habibe, Gupta, Snehalata, Mazumder, Sarmistha, Ray-Chaundhury, Abhik, Li, Tom, Li, Chenglong, Nakano, Ichiro, Rahman, Ruman, Rahman, Cheryl, Smith, Stuart, Macarthur, Donald, Rose, Felicity, Shakesheff, Kevin, Grundy, Richard G., Brenner, Andrew J., Goins, Beth, Bao, Ande, Miller, Jessica, Trevino, Abram, Zuniga, Richard, Phillips, William T., Gilg, Anne G., Bowers, Karen G., Toole, Bryan P., Maria, Bernard L., Leung, Gilberto K., Sun, Stella, Wong, Stanley T., Zhang, Xiao Qin, Pu, Jenny K., Lui, Wai Man, Marino, Anna M., Hussaini, Isa M., Amos, Samson, Simpson, Kendra, Redpath, Gerard T., Lyons, Charles, Dipierro, Charles, Grant, Gerald A., Wilson, Christy, Salami, Sara, Macaroni, Paolo, Li, Shuqin, Park, Ji-Young, Needham, David, Bigner, Darell, Dewhirst, Mark, Ohlfest, John, Gallardo, Jose, Argawal, Sagar, Mittapalli, Rajendar, Donelson, Randy, Elmquist, William F., Nicolaides, Theodore, Hariono, Sujatmi, Barkovich, Krister, Hashizume, Rintaro, Rowitch, David, Weiss, William, Sheer, Denise, Baker, Suzanne, Paugh, Barbara, Waldman, Todd, Li, Huifang, Jones, Chris, Forshew, Tim, James, David, Caroline, Happold, Patrick, Roth, Katrin, Lamszus, Karl, Frei, Ghazaleh, Tabatabai, Michael, Weller, Albrecht, Valerie, Thorsteinsdottir, Jun, Wagner, Ernst, Tonn, Jörg-Christian, Ogris, Manfred, Schichor, Christian, Charest, Gabriel, Paquette, Benoit, Sanche, Léon, Mathieu, David, Fortin, David, Qi, Xiaoyang, Cuttitta, Franck, Chu, Zhengtao, Celerier, Jerome, Pakradouni, Jihane, Rixe, Olivier, Gragg, Ashley, Muller, Sabine, Banerjee, Anuradha, Phillips, Joanna, Prados, Michael, Haas-Kogan, Daphne, Gupta, Nalin, Florence, Lefranc, Gwendoline, Van Goietsenoven, Véronique, Mathieu, Robert, Kiss, Agarwal, Sagar, Mittapalli, Rajendar K., Cen, Ling, Carlson, Brett L., Sarkaria, Jann N., Sengupta, Soma, Weeraratne, Shyamal D., Rallapalli, Sundari, Amani, Vladimir, Pierre-Francois, Jessica, Teider, Natalia, Rotenberg, Alexander, Cook, James, Pomeroy, Scott L., Jenses, Frances, Cho, Yoon-Jae, Hjouj, Mohammad, Last, David, Guez, David, Daniels, Dianne, Lavee, Jacob, Rubinsky, Boris, Mardor, Yael, Serwer, Laura P., Noble, Charles O., Michaud, Karine, Drummond, Daryl C., Ozawa, Tomoko, Zhou, Yu, Marks, James D., Bankiewicz, Krystof, Park, John W., Wang, Weijun, Cho, Heeyeon, Weintraub, Michael, Jhaveri, Niyati, Torres, Shering, Petasis, Nicos, Schonthal, Axel H., Louie, Stan G., Hofman, Florence M., Chen, Thomas C., Grada, Zakaria, Hegde, Meenakshi, Schaffer, Donald R., Ghazi, Alexia, Byrd, Tiara, Dotti, Gianpietro, Wels, Winfried, Heslop, Helen E., Gottschalk, Stephen, Baker, Matthew, Ahmed, Nabil, Hamblett, Kevin J., Kozlosky, Carl J., Liu, Hua, Siu, Sophia, Arora, Taruna, Retter, Marc W., Matsuda, Katherine, Hill, John S., Fanslow, William C., Diaz, Roberto J., Etame, Arnold, Meaghan, O'Reilly, Mainprize, Todd, Smith, Christian, Hynynen, Kullervo, Rutka, James, Pradarelli, Jason, Yoo, Ji Young, Kaka, Azeem, Alvarez-Breckenridge, Christopher, Pan, Quintin, Chiocca, E. Antonio, Teknos, Theodoros, Kaur, Balveen, Lee, Sang Y., Slagle-Webb, Becky, Sheehan, Jonas M., Connor, James R., Cote, Jerome, Lepage, Martin, Gobeil, Fernand, Kleijn, Anne, Balvers, Rutger, Kloezeman, Jenneke, Dirven, Clemens, Lamfers, Martine, Leenstra, Sieger, See, Wendy, Tan, I-Li, Pieper, Russell, Jiang, Hong, White, Erin, Ríos-Vicil, Christian I., Yung, Wai-Kwan A., Gomez-Manzano, Candelaria, Fueyo, Juan, Zemp, Franz J., McKenzie, Brienne A., Mueller, Sabine, Yang, Xiaodong, Smirnov, Ivan, Prados, Micheal, James, David C., Phillips, Joanna J., Berger, Mitchel S., Rowitch, David H., Haas-Kogan, Daphne H., Kennedy, Benjamin, Gopalakrishnan, Vidya, Das, Chandramallika, Taylor, Pete, Kommagani, Ramakrishna, Su, Xiaohua, Aguilera, Dolly, Thomas, Alexandra, Wolff, Johannes, Flores, Elsa, Kadakia, Madhavi, Alkins, Ryan, Broderson, Peter, Sodhi, Rana, Chung, Sylvia A., McDonald, Kerrie L., Shen, Han, Day, Bryan W., Stringer, Brett W., Johns, Terrance, Decollogne, Stéphanie, Teo, Charlie, Hogg, Philip J., Dilda, Pierre J., Patel, Toral R., Zhou, Jiangbing, Piepmeier, Joseph M., Saltzman, W Mark, Vogelbaum, Michael A., Manchanda, Pooja, Ohlfest, John R., Kitange, Gaspar J., Mladek, Ann C., Schroeder, Mark A., Pokorny, Jenny L., Mody, Christopher, Forsyth, Peter, Dasgupta, Tina, James, C. David, Madhankumar, Achuthamangalam B., Webb, Becky Slagle, Park, Annie, Harbaugh, Kimberly, Sheehan, Jonas

مصطلحات موضوعية: Abstracts

الوصف: BACKGROUND: Medulloblastoma is one of the most common malignant tumors of the central nervous system in newborn infants and children and accounts for about 15% to 20% of pediatric brain tumors. Despite current diagnostic and therapeutic advances, the morbidity and mortality rates still remain high. Furthermore, children who survive medulloblastoma are at risk for long-term sequelae related to the neurological effects of the tumor and surgery, radiotherapy, and chemotherapy. Therefore, it is of great importance to identify new anticancer drugs that can significantly assist in improving the survival of children with minimal or no side effects. In this study, our primary objective was to identify and study the efficacy of new structural classes of drugs belonging to a family of steroid biogenesis inhibitors and in the peroxovanadium superfamily. METHODS: We chose to undertake our preclinical testing on malignant pediatric medulloblastoma cell lines. After determining the IC50 values of our experimental drugs, we subjected our preclinical cell line models to a wide variety of cancer assays, including viability/proliferation, cell death, cell cycle regulation and transformation assays. RESULTS AND CONCLUSIONS: Our data so far demonstrate that the panel of new structural classes of drugs examined can significantly affect the viability and transformation of malignant medulloblastoma preclinical cell line models. Most importantly, the toxicity of our drugs was almost devoid in our non-transformed control cell lines. Our current work continues to explore the efficacy of these drugs in additional malignant medulloblastoma preclinical models. This body of work is novel and highly significant in our effort to discover improved treatments for childhood brain tumors.

وصف الملف: text/html

العلاقة: http://neuro-oncology.oxfordjournals.org/cgi/content/short/13/suppl_3/iii107Test; http://dx.doi.org/10.1093/neuonc/nor158Test

الإتاحة: https://doi.org/10.1093/neuonc/nor158Test
http://neuro-oncology.oxfordjournals.org/cgi/content/short/13/suppl_3/iii107Test

المؤلفون: Hamblett, Kevin J.

المصدر: Cancer Drug Discovery and Development ; Innovations for Next-Generation Antibody-Drug Conjugates ; page 163-185 ; ISSN 2196-9906 2196-9914 ; ISBN 9783319781532 9783319781549

الإتاحة: https://doi.org/10.1007/978-3-319-78154-9_7Test

المؤلفون: McDonagh, Charlotte F., Turcott, Eileen, Westendorf, Lori, Webster, Jennifer B., Alley, Stephen C., Kim, Kristine, Andreyka, Jamie, Stone, Ivan, Hamblett, Kevin J., Francisco, Joseph A., Carter, Paul

مصطلحات موضوعية: ORIGINAL ARTICLES

الوصف: The chimeric anti-CD30 IgG 1 , cAC10, conjugated to eight equivalents of monomethyl auristatin E (MMAE) was previously shown to have potent antitumor activity against CD30-expressing tumors xenografts in mice. Moreover, the therapeutic index was increased by lowering the stoichiometry from 8 drugs/antibody down to 2 or 4. Limitations of such ‘partially-loaded’ conjugates are low yield (10–30%) as they are purified from mixtures with variable stoichiometry (0–8 drugs/antibody), and heterogeneity as the 2 or 4 drugs are distributed over eight possible cysteine conjugation sites. Here, the solvent-accessible cysteines that form the interchain disulfide bonds in cAC10 were replaced with serine, to reduce the eight potential conjugation sites down to 4 or 2. These Cys→Ser antibody variants were conjugated to MMAE in near quantitative yield (89–96%) with defined stoichiometries (2 or 4 drugs/antibody) and sites of drug attachment. The engineered antibody–drug conjugates have comparable antigen-binding affinities and in vitro cytotoxic activities with corresponding purified parental antibody–drug conjugates. Additionally, the engineered and parental antibody–drug conjugates have similar in vivo properties including antitumor activity, pharmacokinetics and maximum tolerated dose. Our strategy for generating antibody–drug conjugates with defined sites and stoichiometries of drug loading is potentially broadly applicable to other antibodies as it involves engineering of constant domains.

وصف الملف: text/html

العلاقة: http://peds.oxfordjournals.org/cgi/content/short/19/7/299Test; http://dx.doi.org/10.1093/protein/gzl013Test

الإتاحة: https://doi.org/10.1093/protein/gzl013Test
http://peds.oxfordjournals.org/cgi/content/short/19/7/299Test

المؤلفون: Hamblett, Kevin J., Cochran, Julia, Snead, Katie, Jin, Steven, Yumul, Roma, Simmons, Jessica, Stone, Ivan, Lyski, Ryan, Schrum, Jason P., Lim, Andrea R., Clarke, Astrid

المصدر: Blood; November 2023, Vol. 142 Issue: 1, Number 1 Supplement 1 p1440-1440, 1p

مستخلص: SGN-35C is an antibody drug conjugate composed of an anti-CD30 antibody conjugated to a camptothecin-derived topoisomerase 1 (TOP1) inhibitor payload. SGN-35C was designed to leverage the antibody backbone from brentuximab vedotin (BV) and the novel mechanism of action of camptothecin-derived ADCs. Here, we evaluated the mechanism of action, cytotoxicity, and safety in in vitro and in vivo models.

المؤلفون: Hamblett, Kevin J., Le, Tiep, Rock, Brooke M., Rock, Dan A., Siu, Sophia, Huard, Justin N., Conner, Kip P., Milburn, Robert R., O’Neill, Jason W., Tometsko, Mark E., Fanslow, William C.

المصدر: Molecular Pharmaceutics ; volume 13, issue 7, page 2387-2396 ; ISSN 1543-8384 1543-8392

الإتاحة: https://doi.org/10.1021/acs.molpharmaceut.6b00153Test

المؤلفون: Sun, Michael M. C., Beam, Kevin S., Cerveny, Charles G., Hamblett, Kevin J., Blackmore, Richard S., Torgov, Michael Y., Handley, Felicia G. M., Ihle, Nathan C., Senter, Peter D., Alley, Stephen C.

المصدر: Bioconjugate Chemistry ; volume 16, issue 5, page 1282-1290 ; ISSN 1043-1802 1520-4812

الإتاحة: https://doi.org/10.1021/bc050201yTest

المؤلفون: Hamblett, Kevin J., Press, Oliver W., Meyer, Damon L., Hamlin, Don K., Axworthy, Don, Wilbur, D. Scott, Stayton, Patrick S.

المصدر: Bioconjugate Chemistry ; volume 16, issue 1, page 131-138 ; ISSN 1043-1802 1520-4812

الإتاحة: https://doi.org/10.1021/bc034049gTest

المؤلفون: Hamblett, Kevin J., Kegley, Brian B., Hamlin, Don K., Chyan, Ming-Kuan, Hyre, David E., Press, Oliver W., Wilbur, D. Scott, Stayton, Patrick S.

المصدر: Bioconjugate Chemistry ; volume 13, issue 3, page 588-598 ; ISSN 1043-1802 1520-4812

الإتاحة: https://doi.org/10.1021/bc010087tTest

المؤلفون: Hamblett, Kevin J.¹ kjhamblett@comcast.net, Jacob, Allison P.¹, Gurgel, Jesse L.¹, Tometsko, Mark E.¹, Rock, Brooke M.², Patel, Sonal K.², Milburn, Robert R.³, Siu, Sophia⁴, Ragan, Seamus P.⁵, Rock, Dan A.², Borths, Christopher J.³, O'Neill, Jason W.⁴, Chang, Wesley S.⁶, Weidner, Margaret F.¹, Bio, Matthew M.³, Quon, Kim C.¹, Fanslow, William C.¹

المصدر: Cancer Research. 12/15/2015, Vol. 75 Issue 24, p5329-5340. 12p.

مصطلحات موضوعية: *ANTIBODY-drug conjugates, *CANCER treatment, *MAYTANSINE, *LYSOSOMES, *CYTOPLASM

مستخلص: Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acidlinker- warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody-maytansine ADCs, including adotrastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure-activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens. [ABSTRACT FROM AUTHOR]