The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers

References

• Geng F, Wang Z, Yin H, et al. Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives. Cancer Biother Radiopharm. 2017;32(5):149–160.
   PubMed Web of Science ®Google Scholar
• Mendes M, Sousa JJ, Pais A, et al. Targeted theranostic nanoparticles for brain tumor treatment. Pharmaceutics. 2018;10(4):181.
   PubMed Web of Science ®Google Scholar
• Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;18(4):CD006243.
   Google Scholar
• Yuan M, Huang LL, Chen JH, et al. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther. 2019;4:61.
   PubMed Web of Science ®Google Scholar
• Li P, Jahnke J, Pettit AR, et al. Comparative survival associated with use of targeted vs nontargeted therapy in medicare patients with metastatic renal cell carcinoma. JAMA Netw Open. 2019;2(6):e195806.
   PubMed Web of Science ®Google Scholar
• Nguyen KS, Neal JW, Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol. 2014;5(4):576–587.
   PubMedGoogle Scholar
• Pulte D, Weberpals J, Jansen L, et al. Changes in population-level survival for advanced solid malignancies with new treatment options in the second decade of the 21st century. Cancer. 2019;125(15):2656–2665.
   PubMed Web of Science ®Google Scholar
• Caswell DR, Swanton C. The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. BMC Med. 2017;15(1):133.
   PubMedGoogle Scholar
• Del Carmen S, Sayagues JM, Bengoechea O, et al. Spatio-temporal tumor heterogeneity in metastatic CRC tumors: a mutational-based approach. Oncotarget. 2018;9(76):34279–34288.
   PubMedGoogle Scholar
• Fidler IJ. Biological heterogeneity of cancer: implication to therapy. Hum Vaccin Immunother. 2012;8(8):1141–1142.
   PubMed Web of Science ®Google Scholar
• Kalinowski L, Saunus JMM, Reed AE, et al. Breast cancer heterogeneity in primary and metastatic disease. In: Ahmad A, editor. Breast cancer metastasis and drug resistance: challenges and progress. Cham (Switzerland): Springer International Publishing; 2019. p. 75–104.
   Google Scholar
• Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6(9):714–727.
   PubMed Web of Science ®Google Scholar
• Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol. 2012;6(2):155–176.
   PubMed Web of Science ®Google Scholar
• Crisci SD, Francia R, Mele S, et al. Overview of targeted drugs for mature B-cell non-Hodgkin lymphomas. Front Oncol. 2019;9:443.
   PubMed Web of Science ®Google Scholar
• Estirado EM, Aleman Garcia MA, Schill J, et al. Multivalent ultrasensitive interfacing of supramolecular 1D nanoplatforms. J Am Chem Soc. 2019;141(45):18030–18037.
   PubMed Web of Science ®Google Scholar
• Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins. Science. 1997;278(5337):497–499.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, Hok S, Van Natarajan A, et al. Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin’s lymphoma. Int J Oncol. 2007;31(4):729–740.
   PubMed Web of Science ®Google Scholar
• Balhorn R, Hok S, DeNardo S, et al. Hexa-arginine enhanced uptake and residualization of selective high affinity ligands by Raji lymphoma cells. Mol Cancer. 2009;8:25.
   PubMed Web of Science ®Google Scholar
• Hok S, Natarajan A, Balhorn R, et al. Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin’s lymphoma and leukemia. Bioconjug Chem. 2007;18(3):912–921.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, Natarajan A, Hok S, et al. Nanomolecular HLA-DR10 antibody mimics: a potent system for molecular targeted therapy and imaging. Cancer Biother Radiopharm. 2008;23(6):783–796.
   PubMed Web of Science ®Google Scholar
• Balhorn R, Hok S, Burke PA, et al. Selective high-affinity ligand antibody mimics for cancer diagnosis and therapy: initial application to lymphoma/leukemia. Clin Cancer Res. 2007;13(18):5621s–5628s.
   PubMed Web of Science ®Google Scholar
• Balhorn R, Balhorn MC. Selective high affinity ligands: a new class of targeting agents for cancer imaging and therapy. In: Baum RP, editor. Therapeutic nuclear medicine, in series medical radiology/radiation oncology. Berlin, Germany; Heidelberg, Germany: Springer-Verlag; 2014. p. 139–150.
   Google Scholar
• Au KM, Balhorn R, Balhorn MC, et al. High-performance concurrent chemo-immuno-radiotherapy for the treatment of hematologic cancer through selective high-affinity ligand antibody mimic-functionalized doxorubicin-encapsulated nanoparticles. ACS Cent Sci. 2019;5(1):122–144.
   PubMed Web of Science ®Google Scholar
• Balhorn R, Balhorn MC. Therapeutic applications of the selective high affinity ligand drug SH7139 extend beyond non-Hodgkin’s lymphoma to many other types of solid cancers. Oncotarget. 2020. (In press).
   PubMedGoogle Scholar
• Wan H. An overall comparison of small molecules andlargebiologics in ADME testing. ADMET and DMPK. 2016;4(1):1–22.
   Web of Science ®Google Scholar
• Edwards JA, Jones DB, Evans PR, et al. Differential expression of HLA class II antigens on human fetal and adult lymphocytes and macrophages. Immunology. 1985;55(3):489–500.
   PubMed Web of Science ®Google Scholar
• Rovati B, Mariucci S, Manzoni M, et al. Flow cytometric detection of circulating dendritic cells in healthy subjects. Eur J Histochem. 2008;52(1):45–52.
   PubMed Web of Science ®Google Scholar
• Summers KL, Hock BD, McKenzie JL, et al. Phenotypic characterization of five dendritic cell subsets in human tonsils. Am J Pathol. 2001;159(1):285–295.
   PubMed Web of Science ®Google Scholar
• Toujas L, Delcros JG, Diez E, et al. Human monocyte-derived macrophages and dendritic cells are comparably effective in vitro in presenting HLA class I-restricted exogenous peptides. Immunology. 1997;91(4):635–642.
   PubMed Web of Science ®Google Scholar
• Bernd HW, Ziepert M, Thorns C, et al. Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma - analyses of cases from two prospective randomized clinical trials. Haematologica. 2009;94(11):1569–1580.
   PubMed Web of Science ®Google Scholar
• Feinmesser M, Sulkes A, Morgenstern S, et al. HLA-DR and beta 2 microglobulin expression in medullary and atypical medullary carcinoma of the breast: histopathologically similar but biologically distinct entities. J Clin Pathol. 2000;53(4):286–291.
   PubMed Web of Science ®Google Scholar
• Guy K, Krajewski AS, Dewar AE. Expression of MHC class II antigens in human B-cell leukaemia and non-Hodgkin’s lymphoma. Br J Cancer. 1986;53(2):161–173.
   PubMed Web of Science ®Google Scholar
• Holling TM, Schooten E, Langerak AW, et al. Regulation of MHC class II expression in human T-cell malignancies. Blood. 2004;103(4):1438–1444.
   PubMed Web of Science ®Google Scholar
• Kohchiyama A, Oka D, Ueki H. Expression of human lymphocyte antigen (HLA)-DR on tumor cells in basal cell carcinoma. J Am Acad Dermatol. 1987;16(4):833–838.
   PubMed Web of Science ®Google Scholar
• Kunihiro M, Tanaka S, Haruma K, et al. Combined expression of HLA-DR antigen and proliferating cell nuclear antigen correlate with colorectal cancer prognosis. Oncology. 1998;55(4):326–333.
   PubMed Web of Science ®Google Scholar
• Lovig T, Andersen SN, Thorstensen L, et al. Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis. Br J Cancer. 2002;87(7):756–762.
   PubMed Web of Science ®Google Scholar
• Matoba K, Iizuka N, Gondo T, et al. Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma. Int J Cancer. 2005;115(2):231–240.
   PubMed Web of Science ®Google Scholar
• Rangel LB, Agarwal R, Sherman-Baust CA, et al. Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers. Cancer Biol Ther. 2004;3(10):1021–1027.
   PubMed Web of Science ®Google Scholar
• Redondo M, Ruiz-Cabello F, Concha A, et al. Differential expression of MHC class II genes in lung tumour cell lines. Eur J Immunogenet. 1998;25(6):385–391.
   PubMedGoogle Scholar
• Sadanaga N, Kuwano H, Watanabe M, et al. Local immune response to tumor invasion in esophageal squamous cell carcinoma. The expression of human leukocyte antigen-DR and lymphocyte infiltration. Cancer. 1994;74(2):586–591.
   PubMed Web of Science ®Google Scholar
• Sikorska B, Danilewicz M, Wagrowska-Danilewicz M. HLA-DR expression is a significant prognostic factor in laryngeal cancer. A morphometric study. APMIS. 1999;107(4):383–388.
   PubMed Web of Science ®Google Scholar
• Thomas JA, Iliescu V, Crawford DH, et al. Expression of HLA-DR antigens in nasopharyngeal carcinoma: an immunohistological analysis of the tumour cells and infiltrating lymphocytes. Int J Cancer. 1984;33(6):813–819.
   PubMed Web of Science ®Google Scholar
• van Duinen SG, Ruiter DJ, Broecker EB, et al. Level of HLA antigens in locoregional metastases and clinical course of the disease in patients with melanoma. Cancer Res. 1988;48(4):1019–1025.
   PubMed Web of Science ®Google Scholar
• Cardillo TM, Govindan SV, Zalath MB, et al. IMMU-140, a novel SN-38 antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematologic cancers and malignant melanoma. Mol Cancer Ther. 2018;17(1):150–160.
   PubMed Web of Science ®Google Scholar
• Carlo-Stella C, Di Nicola M, Turco MC, et al. The anti-human leukocyte antigen-DR monoclonal antibody 1D09C3 activates the mitochondrial cell death pathway and exerts a potent antitumor activity in lymphoma-bearing nonobese diabetic/severe combined immunodeficient mice. Cancer Res. 2006;66(3):1799–1808.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, Lamborn KR, Goldstein DS, et al. Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Cancer. 1997;80(S12):2706–2711.
   PubMedGoogle Scholar
• Epstein AL, Marder RJ, Winter JN, et al. Two new monoclonal antibodies, Lym-1 and Lym-2, reactive with human B-lymphocytes and derived tumors, with immunodiagnostic and immunotherapeutic potential. Cancer Res. 1987;47(3):830–840.
   PubMed Web of Science ®Google Scholar
• Hu E, Epstein AL, Naeve GS, et al. A phase 1a clinical trial of LYM-1 monoclonal antibody serotherapy in patients with refractory B cell malignancies. Hematol Oncol. 1989;7(2):155–166.
   PubMed Web of Science ®Google Scholar
• Lin TS, Stock W, Xu H, et al. A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia. Leuk Lymphoma. 2009;50(12):1958–1963.
   PubMed Web of Science ®Google Scholar
• Matsuoka S, Ishii Y, Nakao A, et al. Establishment of a therapeutic anti-pan HLA-class II monoclonal antibody that directly induces lymphoma cell death via large pore formation. PLoS One. 2016;11(3):e0150496.
   PubMed Web of Science ®Google Scholar
• Rose LM, Gunasekera AH, DeNardo SJ, et al. Lymphoma-selective antibody Lym-1 recognizes a discontinuous epitope on the light chain of HLA-DR10. Cancer Immunol Immunother. 1996;43(1):26–30.
   PubMed Web of Science ®Google Scholar
• Rose LM, Deng CT, Scott SL, et al. Critical Lym-1 binding residues on polymorphic HLA-DR molecules. Mol Immunol. 1999;36(11–12):789–797.
   PubMed Web of Science ®Google Scholar
• Schweighofer CD, Tuchscherer A, Sperka S, et al. Clinical safety and pharmacological profile of the HLA-DR antibody 1D09C3 in patients with B cell chronic lymphocytic leukemia and lymphoma: results from a phase I study. Cancer Immunol Immunother. 2012;61(12):2367–2373.
   PubMed Web of Science ®Google Scholar
• Stephens DM, Starodub AN, Byrd JC, et al. Subcutaneous injections of IMMU-114 (anti-HLA-DR IgG4 monoclonal antibody): initial results of a Phase I First-in-Man Study in hematologic malignancies. Blood. 2015;126(23):2740.
   Google Scholar
• Tawara T, Hasegawa K, Sugiura Y, et al. Fully human antibody exhibits pan-human leukocyte antigen-DR recognition and high in vitro/vivo efficacy against human leukocyte antigen-DR-positive lymphomas. Cancer Sci. 2007;98(6):921–928.
   PubMed Web of Science ®Google Scholar
• DeNardo SJ, DeNardo GL, O’Grady LF, et al. Treatment of a patient with B cell lymphoma by I-131 LYM-1 monoclonal antibodies. Int J Biol Markers. 1987;2(1):49–53.
   PubMedGoogle Scholar
• DeNardo SJ, DeNardo GL, O’Grady LF, et al. Treatment of B cell malignancies with 131I Lym-1 monoclonal antibodies. Int J Cancer Suppl. 1988;3:96–101.
   PubMedGoogle Scholar
• DeNardo GL, Lamborn KR, DeNardo SJ, et al. Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies. Cancer Res. 1995;55(23):5893s–5898s.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, O’Donnell RT, Rose LM, et al. Milestones in the development of Lym-1 therapy. Hybridoma. 1999;18(1):1–11.
   PubMedGoogle Scholar
• O’Donnell RT, DeNardo SJ, Miers LA, et al. Combined modality radioimmunotherapy with taxol and 90Y-Lym-1 for Raji lymphoma xenografts. Cancer Biother Radiopharm. 1998;13(5):351–361.
   PubMed Web of Science ®Google Scholar
• O’Donnell RT, DeNardo GL, Kukis DL, et al. A clinical trial of radioimmunotherapy with 67Cu-2IT-BAT-Lym-1 for non-Hodgkin’s lymphoma. J Nucl Med. 1999;40(12):2014–2020.
   PubMed Web of Science ®Google Scholar
• O’Donnell RT, Shen S, Denardo SJ, et al. A phase I study of 90Y-2IT-BAD-Lym-1 in patients with non-Hodgkin’s lymphoma. Anticancer Res. 2000;20(5C):3647–3655.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, Mirick GR, Hok S, et al. Molecular specific and cell selective cytotoxicity induced by a novel synthetic HLA-DR antibody mimic for lymphoma and leukemia. Int J Oncol. 2009;34(2):511–516.
   PubMed Web of Science ®Google Scholar
• Boyum A. Separation of leukocytes from blood and bone marrow. Introduction Scand J Clin Lab Invest Suppl. 1968;97:7.
   PubMedGoogle Scholar
• van Dijk A, Melchers R, Hilkes Y, et al. HLA-DRB sequencing-based typing: an improved protocol which shows complete DRB exon 2 sequences and includes exon 3 of HLA-DRB4/5. Tissue Antigens. 2007;69(1):61–63.
   PubMedGoogle Scholar
• Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–675.
   PubMed Web of Science ®Google Scholar
• Verschuuren G. EC50/IC50 Determination in Excel: Sigmoid or Logistic Curves. YouTube: https://www.youtube.com/watch?v=fMghQw2Ry2c.; 2013.
   Google Scholar
• Douglass EF, Jr., Miller CJ, Sparer G, et al. A comprehensive mathematical model for three-body binding equilibria. J Am Chem Soc. 2013;135(16):6092–6099.
   PubMed Web of Science ®Google Scholar
• Schoemaker RC, van Gerven JM, Cohen AF. Estimating potency for the Emax-model without attaining maximal effects. J Pharmacokinet Biopharm. 1998;26(5):581–593.
   PubMedGoogle Scholar
• Zhang Y, Huo M, Zhou J, et al. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306–314.
   PubMed Web of Science ®Google Scholar
• Boegel S, Lower M, Bukur T, et al. A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines. Oncoimmunology. 2014;3(8):e954893.
   PubMed Web of Science ®Google Scholar
• Balhorn RL, Skorupski KA, Hok S, et al. A selective high affinity ligand (SHAL) designed to bind to an over-expressed human antigen on non-Hodgkin’s lymphoma also binds to canine B-cell lymphomas. Vet Immunol Immunopathol. 2010;137(3–4):235–242.
   PubMed Web of Science ®Google Scholar
• Chang CC, Sun JT, Liou TH, et al. Clinical significance of smudge cells in peripheral blood smears in hematological malignancies and other diseases. Asian Pac J Cancer Prev. 2016;17(4):1847–1850.
   PubMedGoogle Scholar
• Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011;39:W270–W277.
   PubMed Web of Science ®Google Scholar
• Brown JH, Jardetzky TS, Gorga JC, et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993;364(6432):33–39.
   PubMed Web of Science ®Google Scholar
• Smith KJ, Pyrdol J, Gauthier L, et al. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J Exp Med. 1998;188(8):1511–1520.
   PubMed Web of Science ®Google Scholar
• Lechler R, Batchelor R, Lombardi G. The relationship between MHC restricted and allospecific T cell recognition. Immunol Lett. 1991;29(1–2):41–50.
   PubMed Web of Science ®Google Scholar
• Madeleine MM, Brumback B, Cushing-Haugen KL, et al. Human leukocyte antigen class II and cervical cancer risk: a population-based study. J Infect Dis. 2002;186(11):1565–1574.
   PubMed Web of Science ®Google Scholar
• Kubler K, Arndt PF, Wardelmann E, et al. HLA-class II haplotype associations with ovarian cancer. Int J Cancer. 2006;119(12):2980–2985.
   PubMed Web of Science ®Google Scholar
• Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205–1213.
   PubMed Web of Science ®Google Scholar
• Orozco G, Rueda B, Martin J. Genetic basis of rheumatoid arthritis. Biomed Pharmacother. 2006;60(10):656–662.
   PubMed Web of Science ®Google Scholar
• Bhettay E, Martell R, Creemers PC. Association of HLA-DR10 with juvenile chronic arthritis in South Africans of mixed ancestry. Tissue Antigens. 1994;43(1):47–49.
   PubMedGoogle Scholar
• Salazar M, Varela A, Ramirez LA, et al. Association of HLA-DRB1*1602 and DRB1*1001 with Takayasu arteritis in Colombian mestizos as markers of Amerindian ancestry. Int J Cardiol. 2000;75(1):S113–S116.
   PubMedGoogle Scholar
• White AG, Rostom AI. HLA antigens in Arabs with lichen planus. Clin Exp Dermatol. 1994;19(3):236–237.
   PubMed Web of Science ®Google Scholar
• Thibodeau J, Bourgeois-Daigneault MC, Lapointe R. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. 2012;1(6):908–916.
   PubMed Web of Science ®Google Scholar
• Altomonte M, Fonsatti E, Visintin A, et al. Targeted therapy of solid malignancies via HLA class II antigens: a new biotherapeutic approach? Oncogene. 2003;22(42):6564–6569.
   PubMed Web of Science ®Google Scholar
• Renkvist N, Castelli C, Robbins PF, et al. A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother. 2001;50(1):3–15.
   PubMed Web of Science ®Google Scholar
• Sensi M, Anichini A. Unique tumor antigens: evidence for immune control of genome integrity and immunogenic targets for T cell-mediated patient-specific immunotherapy. Clin Cancer Res. 2006;12(17):5023–5032.
   PubMed Web of Science ®Google Scholar
• Dechant M, Bruenke J, Valerius T. HLA class II antibodies in the treatment of hematologic malignancies. Semin Oncol. 2003;30(4):465–475.
   PubMed Web of Science ®Google Scholar
• Hillman GG, Kallinteris NL, Lu X, et al. Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and immuno-consolidation. Cancer Treat Rev. 2004;30(3):281–290.
   PubMed Web of Science ®Google Scholar
• DeNardo GL, DeNardo SJ, Balhorn R. Systemic radiotherapy can cure lymphoma: a paradigm for other malignancies? Cancer Biother Radiopharm. 2008;23(4):383–397.
   PubMed Web of Science ®Google Scholar
• Maccari G, Robinson J, Ballingall K, et al. IPD-MHC 2.0: an improved inter-species database for the study of the major histocompatibility complex. Nucleic Acids Res. 2017;45(D1):D860–D864.
   PubMed Web of Science ®Google Scholar
• Lancaster AK, Single RM, Solberg OD, et al. PyPop update-a software pipeline for large-scale multilocus population genomics. Tissue Antigens. 2007;69(1):192–197.
   PubMedGoogle Scholar
• Solberg OD, Mack SJ, Lancaster AK, et al. Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum Immunol. 2008;69(7):443–464.
   PubMed Web of Science ®Google Scholar
• Koukos PI, Xue LC, Bonvin A. Protein-ligand pose and affinity prediction: lessons from D3R Grand Challenge 3. J Comput Aided Mol Des. 2019;33(1):83–91.
   PubMed Web of Science ®Google Scholar
• Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review. Biophys Rev. 2017;9(2):91–102.
   PubMedGoogle Scholar
• Bee C, Abdiche YN, Pons J, et al. Determining the binding affinity of therapeutic monoclonal antibodies towards their native unpurified antigens in human serum. PLoS One. 2013;8(11):e80501.
   PubMed Web of Science ®Google Scholar