Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer

Science Translational Medicine

Volumn 7, Issue 314, 2015, Pages

  Junttila, Melissa R ^a   Mao, Weiguang ^a   Wang, Xi ^a   Wang, Bu Er ^a   Pham, Thinh ^a   Flygare, John ^a   Yu, Shang Fan ^a   Yee, Sharon ^a   Goldenberg, David ^a   Fields, Carter ^a   Eastham Anderson, Jeffrey ^a   Singh, Mallika ^a,b   Vij, Rajesh ^a   Hongo, Jo Anne ^a   Firestein, Ron ^a,c   Schutten, Melissa ^a   Flagella, Kelly ^a,d   Polakis, Paul ^a   Polson, Andrew G ^a  

^a GENENTECH INC   (United States)

^b Patronus Therapeutics   (United States)

^c HUDSON INSTITUTE OF MEDICAL RESEARCH   (Australia)

^d BIOMARIN PHARMACEUTICAL INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; DOXORUBICIN; LEUCINE RICH CONTAINING G PROTEIN COUPLED RECEPTOR 5; ONCOPROTEIN; PNU 159682; UNCLASSIFIED DRUG; VINCRISTINE; G PROTEIN COUPLED RECEPTOR; IMMUNOTOXIN; LGR5 PROTEIN, HUMAN; LGR5 PROTEIN, MOUSE; LGR5 PROTEIN, RAT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER STEM CELL; CANCER SURVIVAL; CARCINOGENESIS; CELL LINEAGE; CELL VIABILITY; COLON CANCER; CONTROLLED STUDY; DRUG EFFICACY; DRUG SAFETY; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; OVERALL SURVIVAL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; SINGLE DRUG DOSE; TISSUE DISTRIBUTION; TUMOR XENOGRAFT; ANIMAL; C57BL MOUSE; CELL PROLIFERATION; COLONIC NEOPLASMS; DOSE RESPONSE; DRUG EFFECTS; DRUG SCREENING; FEASIBILITY STUDY; GENE EXPRESSION REGULATION; GENETICS; IC50; IMMUNOLOGY; METABOLISM; NUDE MOUSE; PATHOLOGY; SPRAGUE DAWLEY RAT; TIME FACTOR; TRANSGENIC MOUSE; TUMOR CELL LINE; TUMOR SUPPRESSOR GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL PROLIFERATION; COLONIC NEOPLASMS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEASIBILITY STUDIES; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, APC; IMMUNOTOXINS; INHIBITORY CONCENTRATION 50; MALE; MICE, INBRED C57BL; MICE, NUDE; MICE, TRANSGENIC; NEOPLASTIC STEM CELLS; RATS, SPRAGUE-DAWLEY; RECEPTORS, G-PROTEIN-COUPLED; TIME FACTORS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84947738848     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aac7433     Document Type: Article

References (32)

1. L. V. Nguyen, R. Vanner, P. Dirks, C. J. Eaves, Cancer stem cells: An evolving concept. Nat. Rev. Cancer 12, 133-143 (2012).
2. A. Beck, J. Lambert, M. Sun, K. Lin, Fourth World Antibody-Drug Conjugate Summit: February 29-March 1, 2012, Frankfurt, Germany. MAbs 4, 637-647 (2012).
3. A. Mullard, Maturing antibody-drug conjugate pipeline hits 30. Nat. Rev. Drug Discov. 12, 329-332 (2013).
4. N. Barker, J. H. van Es, J. Kuipers, P. Kujala, M. van den Born, M. Cozijnsen, A. Haegebarth, J. Korving, H. Begthel, P. J. Peters, H. Clevers, Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007 (2007).
5. + stem cell activity in mouse intestinal adenomas. Science 337, 730-735 (2012).
6. N. Barker, R. A. Ridgway, J. H. van Es, M. van de Wetering, H. Begthel, M. van den Born, E. Danenberg, A. R. Clarke, O. J. Sansom, H. Clevers, Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608-611 (2009).
7. F. el Marjou, K.-P. Janssen, B. H.-J. Chang, M. Li, V. Hindie, L. Chan, D. Louvard, P. Chambon, D. Metzger, S. Robine, Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186-193 (2004).
8. A. Haegebarth, H. Clevers, Wnt signaling, Lgr5, and stem cells in the intestine and skin. Am. J. Pathol. 174, 715-721 (2009).
9. A. Ng, S. Tan, G. Singh, P. Rizk, Y. Swathi, T. Z. Tan, R. Y.-J. Huang, M. Leushacke, N. Barker, Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nat. Cell Biol. 16, 745-757 (2014).
10. T. McClanahan, S. Koseoglu, K. Smith, J. Grein, E. Gustafson, S. Black, P. Kirschmeier, A. A. Samatar, Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol. Ther. 5, 419-426 (2006).
11. + liver stem cells induced by Wnt-driven regeneration. Nature 494, 247-250 (2013).
12. J. L. Ziskin, D. Dunlap, M. Yaylaoglu, I. K. Fodor, W. F. Forrest, R. Patel, N. Ge, G. G. Hutchins, J. K. Pine, P. Quirke, H. Koeppen, A. M. Jubb, In situ validation of an intestinal stem cell signature in colorectal cancer. Gut 62, 1012-1023 (2012).
13. P. Carter, L. Presta, C. M. Gorman, J. B. Ridgway, D. Henner, W. L. Wong, A. M. Rowland, C. Kotts, M. E. Carver, H. M. Shepard, Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. U.S.A. 89, 4285-4289 (1992).
14. P. D. Senter, E. L. Sievers, The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat. Biotechnol. 30, 631-637 (2012).
15. L. Quintieri, M. Fantin, P. Palatini, S. De Martin, A. Rosato, M. Caruso, C. Geroni, M. Floreani, In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: A comparison with human liver microsomes. Biochem. Pharmacol. 76, 784-795 (2008).
16. J. R. Junutula, H. Raab, S. Clark, S. Bhakta, D. D. Leipold, S. Weir, Y. Chen, M. Simpson, S. P. Tsai, M. S. Dennis, Y. Lu, Y. G. Meng, C. Ng, J. Yang, C. C. Lee, E. Duenas, J. Gorrell, V. Katta, A. Kim, K. McDorman, K. Flagella, R. Venook, S. Ross, S. D. Spencer, W. Lee Wong, H. B. Lowman, R. Vandlen, M. X. Sliwkowski, R. H. Scheller, P. Polakis, W. Mallet, Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925-932 (2008).
17. B. M. Tijink, J. Buter, R. de Bree, G. Giaccone, M. S. Lang, A. Staab, C. R. Leemans, G. A. M. S. van Dongen, A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin. Cancer Res. 12, 6064-6072 (2006).
18. J. C. Mirsalis, J. Schindler-Horvat, J. R. Hill, J. E. Tomaszewski, S. J. Donohue, C. A. Tyson, Toxicity of dolastatin 10 in mice, rats and dogs and its clinical relevance. Cancer Chemother. Pharmacol. 44, 395-402 (1999).
19. A. R. Moser, H. C. Pitot, W. F. Dove, A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322-324 (1990).
20. E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, D. A. Tuveson, Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243-3248 (2001).
21. I. B. Enquist, Z. Good, A. M. Jubb, G. Fuh, X. Wang, M. R. Junttila, E. L. Jackson, K. G. Leong, Lymph node-independent liver metastasis in a model of metastatic colorectal cancer. Nat. Commun. 5, 3530 (2014).
22. O. J. Sansom, V. Meniel, J. A. Wilkins, A. M. Cole, K. A. Oien, V. Marsh, T. J. Jamieson, C. Guerra, G. H. Ashton, M. Barbacid, A. R. Clarke, Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl. Acad. Sci. U.S.A. 103, 14122-14127 (2006).
23. K.-P. Janssen, P. Alberici, H. Fsihi, C. Gaspar, C. Breukel, P. Franken, C. Rosty, M. Abal, F. ElMarjou, R. Smits, D. Louvard, R. Fodde, S. Robine, APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131, 1096-1109 (2006).
24. J. Muñoz, D. E. Stange, A. G. Schepers, M. van de Wetering, B.-K. Koo, S. Itzkovitz, R. Volckmann, K. S. Kung, J. Koster, S. Radulescu, K. Myant, R. Versteeg, O. J. Sansom, J. H. van Es, N. Barker, A. van Oudenaarden, S. Mohammed, A. J. R. Heck, H. Clevers, The Lgr5 intestinal stem cell signature: Robust expression of proposed quiescent '+4' cell markers. EMBO J. 31, 3079-3091 (2012).
25. Y. Nakanishi, H. Seno, A. Fukuoka, T. Ueo, Y. Yamaga, T. Maruno, N. Nakanishi, K. Kanda, H. Komekado, M. Kawada, A. Isomura, K. Kawada, Y. Sakai, M. Yanagita, R. Kageyama, Y. Kawaguchi, M. M. Taketo, S. Yonehara, T. Chiba, Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat. Genet. 45, 98-103 (2013).
26. H. Tian, B. Biehs, S. Warming, K. G. Leong, L. Rangell, O. D. Klein, F. J. de Sauvage, A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255-259 (2011).
27. E. Oroudjev, M. Lopus, L. Wilson, C. Audette, C. Provenzano, H. Erickson, Y. Kovtun, R. Chari, M. A. Jordan, Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 9, 2700-2713 (2010).
28. + stem cells are indispensable for radiation-induced intestinal regeneration, Cell Stem Cell 14, 149-159 (2013).
29. D. Li, K. A. Poon, S.-F. Yu, R. Dere, M. Go, J. Lau, B. Zheng, K. Elkins, D. Danilenko, K. R. Kozak, P. Chan, J. Chuh, X. Shi, D. Nazzal, F. Fuh, J. McBride, V. Ramakrishnan, R. de Tute, A. Rawstron, A. S. Jack, R. Deng, Y.-W. Chu, D. Dornan, M. Williams, W. Ho, A. Ebens, S. Prabhu, A. G. Polson, DCDT2980S, an anti-CD22-monomethyl auristatin E antibody-drug conjugate, is a potential treatment for non-Hodgkin lymphoma. Mol. Cancer Ther. 12, 1255-1265 (2013).
30. L. Gautier, L. Cope, B. M. Bolstad, R. A. Irizarry, affy-Analysis of Affymetrix GeneChip data at the probe level, Bioinformatics 20, 307-315 (2004).
31. A. G. Polson, J. Calemine-Fenaux, P. Chan, W. Chang, E. Christensen, S. Clark, F. J. de Sauvage, D. Eaton, K. Elkins, J. M. Elliott, G. Frantz, R. N. Fuji, A. Gray, K. Harden, G. S. Ingle, N. M. Kljavin, H. Koeppen, C. Nelson, S. Prabhu, H. Raab, S. Ross, D. S. Slaga, J.-P. Stephan, S. J. Scales, S. D. Spencer, R. Vandlen, B. Wranik, S.-F. Yu, B. Zheng, A. Ebens, Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: Target and linker-drug selection. Cancer Res. 69, 2358-2364 (2009).
32. E. M. Brey, Z. Lalani, C. Johnston, M. Wong, L. V. McIntire, P. J. Duke, C. W. Patrick Jr., Automated selection of DAB-labeled tissue for immunohistochemical quantification. J. Histochem. Cytochem. 51, 575-584 (2003).