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Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.

Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J
Proc Natl Acad Sci U S A 110 17832-7 (2013)
Cited: 15 times
EuropePMC logo PMID: 24127596

Abstract

Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as major drivers of gastrointestinal stromal tumors and a subset of acute myeloid leukemia, melanoma, and other cancers. Although treatment of these cancers with tyrosine kinase inhibitors shows dramatic responses and durable disease control, drug resistance followed by clinical progression of disease eventually occurs in virtually all patients. In this report, we describe inhibitory KIT antibodies that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap with an epitope in D4 that mediates homotypic interactions essential for KIT activation. Crystal structures of the anti-KIT antibody in complex with KIT D4 and D5 allowed design of affinity-matured libraries that were used to isolate variants with increased affinity and efficacy. Isolated antibodies showed KIT inhibition together with suppression of cell proliferation driven by ligand-stimulated WT or constitutively activated oncogenic KIT mutant. These antibodies represent a unique therapeutic approach and a step toward the development of "naked" or toxin-conjugated KIT antibodies for the treatment of KIT-driven cancers.

Articles - 4k9e mentioned but not cited (1)

  1. Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region. Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J. Proc. Natl. Acad. Sci. U.S.A. 110 17832-17837 (2013)


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  1. Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors. Stahl M, Gedrich R, Peck R, LaVallee T, Eder JP. Immunotherapy 8 767-774 (2016)
  2. BITES and CARS and checkpoints, oh my! Updates regarding immunotherapy for myeloid malignancies from the 2018 annual ASH meeting. Przespolewski AC, Griffiths EA. Blood Rev 43 100654 (2020)

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  2. Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Leppänen VM, Saharinen P, Alitalo K. Proc. Natl. Acad. Sci. U.S.A. 114 4376-4381 (2017)
  3. Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1. Felix J, De Munck S, Verstraete K, Meuris L, Callewaert N, Elegheert J, Savvides SN. Structure 23 1621-1631 (2015)
  4. Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Moore JO, Lemmon MA, Ferguson KM. Proc. Natl. Acad. Sci. U.S.A. 114 4382-4387 (2017)
  5. KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells. London CA, Gardner HL, Rippy S, Post G, La Perle K, Crew L, Lopresti-Morrow L, Garton AJ, McMahon G, LaVallee TM, Gedrich R. Clin. Cancer Res. 23 2565-2574 (2017)
  6. Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells. Magnani CF, Myburgh R, Brunn S, Chambovey M, Ponzo M, Volta L, Manfredi F, Pellegrino C, Pascolo S, Miskey C, Ivics Z, Shizuru JA, Neri D, Manz MG. Mol Ther Oncolytics 30 56-71 (2023)
  7. Anti-KIT DNA Aptamer for Targeted Labeling of Gastrointestinal Stromal Tumor. Banerjee S, Yoon H, Yebra M, Tang CM, Gilardi M, Shankara Narayanan JS, White RR, Sicklick JK, Ray P. Mol Cancer Ther 19 1173-1182 (2020)
  8. Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG. Leukemia 34 2688-2703 (2020)
  9. Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition. Shi X, Sousa LP, Mandel-Bausch EM, Tome F, Reshetnyak AV, Hadari Y, Schlessinger J, Lax I. Proc. Natl. Acad. Sci. U.S.A. 113 E4784-93 (2016)
  10. Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5. Le Gall M, Crépin R, Neiveyans M, Auclair C, Fan Y, Zhou Y, Marks JD, Pèlegrin A, Poul MA. Mol. Cancer Ther. 14 2595-2605 (2015)
  11. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Casirati G, Cosentino A, Mucci A, Salah Mahmoud M, Ugarte Zabala I, Zeng J, Ficarro SB, Klatt D, Brendel C, Rambaldi A, Ritz J, Marto JA, Pellin D, Bauer DE, Armstrong SA, Genovese P. Nature 621 404-414 (2023)
  12. Inhibition of Marburg Virus RNA Synthesis by a Synthetic Anti-VP35 Antibody. Amatya P, Wagner N, Chen G, Luthra P, Shi L, Borek D, Pavlenco A, Rohrs H, Basler CF, Sidhu SS, Gross ML, Leung DW. ACS Infect Dis 5 1385-1396 (2019)


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