EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia

Abstract

The human EphA3 gene was discovered in a pre-B acute lymphoblastic leukemia (pre-B-ALL) using the EphA3-specific monoclonal antibody (mAb), IIIA4, which binds and activates both human and mouse EphA3. We use two models of human pre-B-ALL to examine EphA3 function, demonstrating effects on pre-B-cell receptor signaling. In therapeutic targeting studies, we demonstrated antitumor effects of the IIIA4 mAb in EphA3-expressing leukemic xenografts and no antitumor effect in the xenografts with no EphA3 expression providing evidence that EphA3 is a functional therapeutic target in pre-B-ALL. Here we show that the therapeutic effect of the anti-EphA3 antibody was greatly enhanced by adding an α-particle-emitting 213 Bismuth payload.Cell Stem Cell. 2012 Sep 7;11(3):359-72. (PMID: 22863534); Cancer Cell. 2013 Feb 11;23(2):238-48. (PMID: 23410976); Cold Spring Harb Perspect Biol. 2010 May;2(5):a001875. (PMID: 20452960); Biochem Biophys Res Commun. 2002 Oct 18;298(1):87-94. (PMID: 12379224); Expert Opin Drug Deliv. 2016;13(3):401-19. (PMID: 26654403); Nat Rev Cancer. 2010 Mar;10(3):165-80. (PMID: 20179713); Science. 2011 Jul 8;333(6039):228-33. (PMID: 21617041); J Biol Chem. 1992 Feb 15;267(5):3262-7. (PMID: 1737782); Leuk Lymphoma. 1999 Apr;33(3-4):371-6. (PMID: 10221518); Leuk Res. 1992 Jun-Jul;16(6-7):655-63. (PMID: 1378917); J Cell Biol. 2004 Mar 1;164(5):661-6. (PMID: 14993233); Nature. 2015 May 21;521(7552):357-61. (PMID: 25799995); Oncotarget. 2014 May 30;5(10):3145-58. (PMID: 24762669); J Neurosci. 2004 Jul 14;24(28):6248-57. (PMID: 15254079); Blood. 1999 Oct 1;94(7):2477-86. (PMID: 10498621); Leuk Res. 2016 Nov;50:123-131. (PMID: 27736729); Growth Factors. 2000;18(1):63-78. (PMID: 10831073); Cancer Res. 2014 Aug 15;74(16):4470-81. (PMID: 25125683); PLoS One. 2015 Jun 17;10(6):e0130692. (PMID: 26083390); Int J Dev Biol. 2002;46(4):375-84. (PMID: 12141423); Bioorg Med Chem. 1997 Oct;5(10):1925-34. (PMID: 9370037); Cancer Res. 2005 Aug 1;65(15):6745-54. (PMID: 16061656); Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):50-3. (PMID: 21454190); Nat Rev Drug Discov. 2014 Jan;13(1):39-62. (PMID: 24378802); Nat Rev Mol Cell Biol. 2005 Jun;6(6):462-75. (PMID: 15928710); Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1611-5. (PMID: 1311845); New Biol. 1991 Aug;3(8):769-78. (PMID: 1657122); Dev Cell. 2004 Oct;7(4):465-80. (PMID: 15469835); Growth Factors. 2014 Dec;32(6):223-35. (PMID: 25413948); Leukemia. 2016 Jun;30(6):1246-54. (PMID: 26847027). Linking ISSN: 08876924. Subset: MEDLINE; Date of Electronic Publication: 2016 Dec 06. Current Imprints: Publication: 2000- : London : Nature Publishing Group, Specialist Journals; Original Imprints: Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- <br />