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BioDrugs

, Volume 32, Issue 5, pp 481–497 | Cite as

Small-Molecule Immune Checkpoint Inhibitors Targeting PD-1/PD-L1 and Other Emerging Checkpoint Pathways

  • Pottayil G. Sasikumar
  • Murali Ramachandra
Review Article

Abstract

Advances in harnessing the immune system for cancer treatment have been spectacular in recent years as witnessed by the approval of a number of antibodies targeting the PD-1/PD-L1 immune checkpoint pathway spanning an expanding list of indications. However, it is well recognized that while these antibodies show impressive clinical activity, they suffer from shortcomings including the failure to show response in a majority of patients, their need to be administered by intravenous injection, and immune-related adverse events due to the breaking of immune self-tolerance. Small-molecule-based therapeutic approaches offer the potential to address the shortcomings of these antibody-based checkpoint inhibitors. In the first part of this review, we discuss the rationale for small-molecule-based checkpoint therapy followed by efforts on the discovery of small-molecule-based approaches targeting the PD-1/PD-L1 axis and other immune checkpoint pathways. In the latter part of the article, we describe small-molecule inhibitors simultaneously targeting two non-redundant checkpoint inhibitor pathways as an approach to improve the response rate. A brief review of the progress of an oral small-molecule checkpoint inhibitor currently in clinical development is presented at the end.

Notes

Acknowledgements

We thank Tim Wyant (from Curis, Inc.) for his review and useful suggestions on this manuscript.

Compliance with Ethical Standards

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Pottayil G. Sasikumar and Murali Ramachandra are full-time employees of Aurigene, which holds multiple patents related to small-molecule immune checkpoint inhibitors.

References

  1. 1.
    Shekarian T, Valsesia-Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune system rather than cancer cells. Mutagenesis. 2015;30:205–11.CrossRefGoogle Scholar
  2. 2.
    Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432–3.CrossRefGoogle Scholar
  3. 3.
    Jardim DL, Gagliato DM, Giles FJ, Kurzrock R. Analysis of drug development paradigms for immune checkpoint inhibitors. Clin Cancer Res. 2017;clincanres.1970.2017.Google Scholar
  4. 4.
    LaFleur MW, Muroyama Y, Drake CG, Sharpe AH. Inhibitors of the PD-1 pathway in tumor therapy. J Immunol. 2018;200:375–83.CrossRefGoogle Scholar
  5. 5.
    Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91.PubMedGoogle Scholar
  6. 6.
    Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I Study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.CrossRefGoogle Scholar
  7. 7.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.CrossRefGoogle Scholar
  8. 8.
    Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRefGoogle Scholar
  9. 9.
    Kourie HR, Klastersky J. Immune checkpoint inhibitors side effects and management. Immunotherapy. 2016;8:799–807.CrossRefGoogle Scholar
  10. 10.
    Day D, Hansen AR. Immune-related adverse events associated with immune checkpoint inhibitors. BioDrugs. 2016;30:571–84.CrossRefGoogle Scholar
  11. 11.
    Moya-Horno I, Viteri S, Karachaliou N, Rosell R. Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC). Ther Adv Med Oncol [Internet]. 2018;10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784559/. Cited 28 Jun 2018.
  12. 12.
    Merryman RW, Armand P, Wright KT, Rodig SJ. Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma. Blood Adv. 2017;1:2643–54.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 1990;50:814s–9s.PubMedGoogle Scholar
  14. 14.
    Johnson CB, Win SY. Combination therapy with PD-1/PD-L1 blockade: an overview of ongoing clinical trials. Oncoimmunology. 2018;7:e1408744.CrossRefGoogle Scholar
  15. 15.
    Song M, Chen X, Wang L, Zhang Y. Future of anti-PD-1/PD-L1 applications: combinations with other therapeutic regimens. Chin J Cancer Res. 2018;30:157–72.CrossRefGoogle Scholar
  16. 16.
    Homet Moreno B, Ribas A. Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer. 2015;112:1421–7.CrossRefGoogle Scholar
  17. 17.
    Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.CrossRefGoogle Scholar
  18. 18.
    Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23:551–5.CrossRefGoogle Scholar
  19. 19.
    Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment—the more the better? Eur J Cancer. 2017;74:55–72.CrossRefGoogle Scholar
  20. 20.
    Liu X, Zhou Q, Xu Y, Chen M, Zhao J, Wang M, et al. Harness the synergy between targeted therapy and immunotherapy: what have we learned and where are we headed? Oncotarget. 2017;8:86969–84.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Ros XR, Vermeulen L. Turning cold tumors hot by blocking TGF-β. Trends in Cancer. 2018;4:335–7.CrossRefGoogle Scholar
  22. 22.
    Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.CrossRefGoogle Scholar
  23. 23.
    Sasikumar P, Sudarshan NS, Gowda N, Samiulla DS, Ramachandra R, Chandrasekhar T, et al. Abstract 4861: oral immune checkpoint antagonists targeting PD-L1/VISTA or PD-L1/Tim3 for cancer therapy. Cancer Res. 2016;76:4861.CrossRefGoogle Scholar
  24. 24.
    Sasikumar P, Sudarshan N, Ramachandra R, Gowda N, Samiulla D, Bilugudi P, et al. Pre-clinical efficacy in multiple syngeneic models with oral immune checkpoint antagonists targeting PD-L1 and TIM-3. Eur J Cancer. 2016;69:S98.CrossRefGoogle Scholar
  25. 25.
    Andrews A. Treating with checkpoint inhibitors—figure $1 million per patient. Am Health Drug Benefits. 2015;8:9.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Zak KM, Kitel R, Przetocka S, Golik P, Guzik K, Musielak B, et al. Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure. 2015;23:2341–8.CrossRefGoogle Scholar
  27. 27.
    Sharpe AH, Butte MJ, Oyama S. Modulators of immunoinhibitory receptor pd-1, and methods of use thereof [Internet]. 2011. https://patents.google.com/patent/WO2011082400A2/en?oq=WO2011082400. Cited 29 Jun 2018.
  28. 28.
    Sasikumar PGN, Ramachandra M. Immunosuppression modulating compounds [Internet]. 2014. https://patents.google.com/patent/US8907053B2/en?oq=US8907053B2. Cited 29 Jun 2018.
  29. 29.
    Lin DY-W, Tanaka Y, Iwasaki M, Gittis AG, Su H-P, Mikami B, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci USA. 2008;105:3011–6.CrossRefGoogle Scholar
  30. 30.
    Sasikumar PGN, Ramachandra M, Vadlamani SK, SHRIMALI KR, Subbarao K. Therapeutic compounds for immunomodulation [Internet]. 2012. https://patents.google.com/patent/WO2012168944A1/en?oq=WO2012168944. Cited 19 Jun 2018.
  31. 31.
    Sasikumar PGN, Ramachandra M. Immunomodulating cyclic compounds from the bc loop of human pd1 [Internet]. 2013. https://patents.google.com/patent/WO2013144704A1/en?oq=WO2013144704. Cited 19 Jun 2018.
  32. 32.
    Miller MM, Mapelli C, Allen MP, Bowsher MS, Boy KM, Gillis EP, et al. Macrocyclic inhibitors of the pd-1/pd-l1 and cd80(b7-1)/pd-l1 protein/protein interactions [Internet]. 2014. https://patents.google.com/patent/WO2014151634A1/en?oq=WO2014151634. Cited 19 Jun 2018.
  33. 33.
    Magiera-Mularz K, Skalniak L, Zak KM, Musielak B, Rudzinska-Szostak E, Berlicki Ł, et al. Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint. Angew Chem Int Ed. 2017;56:13732–5.CrossRefGoogle Scholar
  34. 34.
    Chupak LS, Zheng X. Compounds useful as immunomodulators [Internet]. 2015. https://patents.google.com/patent/WO2015034820A1/en?oq=WO2015034820. Cited 19 Jun 2018.
  35. 35.
    Chupak LS, Ding M, Martin SW, Zheng X, Hewawasam P, Connolly TP, et al. Compounds useful as immunomodulators [Internet]. 2015. https://patents.google.com/patent/WO2015160641A2/en?oq=WO2015160641. Cited 19 Jun 2018.
  36. 36.
    Skalniak L, Zak KM, Guzik K, Magiera K, Musielak B, Pachota M, et al. Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells. Oncotarget. 2017;8:72167–81.CrossRefGoogle Scholar
  37. 37.
    Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators [Internet]. 2015. https://patents.google.com/patent/WO2015033301A1/en?oq=WO2015033301. Cited 19 Jun 2018.
  38. 38.
    Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. 1,2,4-oxadiazole derivatives as immunomodulators [Internet]. 2015. https://patents.google.com/patent/WO2015033299A1/en?oq=WO2015033299. Cited 19 Jun 2018.
  39. 39.
    Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. Immunomodulating peptidomimetic derivatives [Internet]. 2015. https://patents.google.com/patent/WO2015036927A1/en?oq=WO2015036927+. Cited 19 Jun 2018.
  40. 40.
    Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. Cyclic peptidomimetic compounds as immunomodulators [Internet]. 2015. https://patents.google.com/patent/WO2015033303A1/en?oq=WO2015033303. Cited 19 Jun 2018.
  41. 41.
    Sasikumar PGN, Ramachandra M, NAREMADDEPALLI SSS. Therapeutic immunomodulating compounds [Internet]. 2015. https://patents.google.com/patent/WO2015044900A1/en?oq=WO2015044900. Cited 19 Jun 2018.
  42. 42.
    Sasikumar PGN, Ramachandra M, PRASAD A, Naremaddepalli SSS. 3-substituted 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators [Internet]. 2016. https://patents.google.com/patent/WO2016142894A1/en?oq=WO2016142894. Cited 19 Jun 2018.
  43. 43.
    Chang H-N, Liu B-Y, Qi Y-K, Zhou Y, Chen Y-P, Pan K-M, et al. Blocking of the PD-1/PD-L1 interaction by a D-peptide antagonist for cancer immunotherapy. Angew Chem Int Ed Engl. 2015;54:11760–4.CrossRefGoogle Scholar
  44. 44.
    Guzik K, Zak KM, Grudnik P, Magiera K, Musielak B, Törner R, et al. Small-Molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) interaction via transiently induced protein states and dimerization of PD-L1. J Med Chem. 2017;60:5857–67.CrossRefGoogle Scholar
  45. 45.
    Yeung K-S, Grant-Young KA, Sun L-Q, Langley DR, St LDR, Scola PM. Compounds useful as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018118848A1/en?oq=WO2018118848. Cited 15 Aug 2018.
  46. 46.
    QI C, Konkol LC, Wu L, LAJKIEWICZ N, He C, Xiao K, et al. Bicyclic heteroaromatic compounds as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018119286A1/en?oq=WO2018119286. Cited 15 Aug 2018.
  47. 47.
    Wu L, Li J, QI C, Zhang F, Li Z, Zhu W, et al. Benzooxazole derivatives as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018119266A1/en?oq=WO2018119266. Cited 15 Aug 2018.
  48. 48.
    Lu L, Zhang F, Li J, Wang H, Xiao K, Wu L, et al. Heterocyclic compounds derivatives as pd-l1 internalization inducers [Internet]. 2018. https://patents.google.com/patent/WO2018119263A1/en?oq=WO2018119263. Cited 15 Aug 2018.
  49. 49.
    Wu L, Shen B, Xu M, Yao W. Triazolo[1,5-a]pyridine derivatives as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018119236A1/en?oq=WO2018119236. Cited 15 Aug 2018.
  50. 50.
    Liu PC, VOLGINA A, Wynn R, Zolotarjova N, Wu L, Xiao K, et al. Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers [Internet]. 2018. https://patents.google.com/patent/WO2018119224A1/en?oq=WO2018119224. Cited 15 Aug 2018.
  51. 51.
    Wu L, Yu Z, Zhang F, Yao W. Pyridine derivatives as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018119221A1/en?oq=WO2018119221. Cited 2018 Aug 15.
  52. 52.
    Gillman KW, Goodrich J, Langley DR, Scola PM. Immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018085750A3/en?oq=WO2018085750+. Cited 15 Aug 2018.
  53. 53.
    Webber SE, Almassy RJ. Immune checkpoint inhibitors, compositions and methods thereof [Internet]. 2018. https://patents.google.com/patent/US20180065917A1/en?oq=US20180065917. Cited 19 Jun 2018.
  54. 54.
    Sasikumar PGN, PRASAD A, Naremaddepalli SSS, Ramachandra M. Cyclic substituted-1,3,4-oxadiazole and thiadiazole compounds as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018051255A1/en?oq=WO2018051255. Cited 19 Jun 2018.
  55. 55.
    Sasikumar PGN, PRASAD A, Naremaddepalli SSS, Ramachandra M. Cyclic substituted-1,2,4-oxadiazole compounds as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018051254A1/en?oq=WO2018051254. Cited 19 Jun 2018.
  56. 56.
    MEI S, Wu L, Zhang F, Yao W. Heterocyclic compounds as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018044783A1/en?oq=WO2018044783. Cited 19 Jun 2018.
  57. 57.
    Wang M. Symmetric or semi-symmetric compounds useful as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018026971A1/en?oq=WO2018026971. Cited 19 Jun 2018.
  58. 58.
    Yu Z, Wu L, Yao W. Heterocyclic compounds as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018013789A1/en?oq=WO2018013789. Cited 19 Jun 2018.
  59. 59.
    Passeron T, Benhida R, Dao P, De DGM, Martin A. 4-anilino-quinoline compounds as anti-cancer agents [Internet]. 2018. https://patents.google.com/patent/WO2018007648A1/en?oq=WO2018007648. Cited 19 Jun 2018.
  60. 60.
    Wang Y, Xu Z, Wu T, He M, Zhang N. Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof [Internet]. 2018. https://patents.google.com/patent/WO2018006795A1/en?oq=WO2018006795. Cited 19 Jun 2018.
  61. 61.
    Yeung K-S, Grant-Young KA, Zhu J, Saulnier MG, Frennesson DB, Meng Z, et al. 1,3-Dihydroxy-phenyl derivatives useful as immunomodulators [Internet]. 2018. https://patents.google.com/patent/WO2018009505A1/en?oq=WO2018009505. Cited 19 Jun 2018.
  62. 62.
    Lange C, Malathong V, Mcmurtrie DJ, Punna S, Singh R, Yang J, et al. Immunomodulator compounds [Internet]. 2018. https://patents.google.com/patent/WO2018005374A1/en?oq=WO2018005374. Cited 19 Jun 2018.
  63. 63.
    Xiao K, Zhang F, Wu L, Yao W. Heterocyclic compounds as immunomodulators [Internet]. 2017. https://patents.google.com/patent/WO2017222976A1/en?oq=WO2017222976. Cited 19 Jun 2018.
  64. 64.
    Miller MM, Allen MP, Li L, Bowsher MS, Gillis EP, Mull E, et al. Macrocyclic inhibitors of the pd-1/pd-l1 and cd80/pd-l1 protein/protein interactions [Internet]. 2017. https://patents.google.com/patent/WO2017176608A1/en?oq=WO2017176608. Cited 19 Jun 2018.
  65. 65.
    Allen MP, Gillis EP, Langley DR, Miller MM, Mull E, Sun L-Q, et al. Immunomodulators [Internet]. 2017. https://patents.google.com/patent/WO2017151830A1/en?oq=WO2017151830. Cited 19 Jun 2018.
  66. 66.
    Dömling A. Inhibitors of the pd-1/pd-l1 protein/protein interaction [Internet]. 2017. https://patents.google.com/patent/WO2017118762A1/en?oq=WO2017118762. Cited 19 Jun 2018.
  67. 67.
    Wu L, Yu Z, Zhang F, Yao W. N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators [Internet]. 2017. https://patents.google.com/patent/WO2017106634A1/en?oq=WO2017106634. Cited 19 Jun 2018.
  68. 68.
    Yeung K-S, Connolly TP, Frennesson DB, Grant-Young KA, Hewawasam P, Langley DR, et al. Compounds useful as immunomodulators [Internet]. 2017. https://patents.google.com/patent/WO2017066227A1/en?oq=WO2017066227. Cited 19 Jun 2018.
  69. 69.
    Li J, Wu L, Yao W. Heterocyclic compounds as immunomodulators [Internet]. 2017. https://patents.google.com/patent/WO2017087777A1/en?oq=WO2017087777. Cited 19 Jun 2018.
  70. 70.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.CrossRefGoogle Scholar
  71. 71.
    Kavecansky J. Beyond checkpoint inhibitors: the next generation of immunotherapy in oncology. Am J Hematol Oncol® [Internet]. 2017;13. http://www.gotoper.com/publications/ajho/2017/2017feb/beyond-checkpoint-inhibitors-the-next-generation-of-immunotherapy-in-oncology. Cited 16 Jun 2018.
  72. 72.
    Hahn AW, Gill DM, Pal SK, Agarwal N. The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy. 2017;9:681–92.CrossRefGoogle Scholar
  73. 73.
    Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med. 2011;208:577–92.CrossRefGoogle Scholar
  74. 74.
    Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O’Connell S, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014;74:1924–32.CrossRefGoogle Scholar
  75. 75.
    Flies DB, Wang S, Xu H, Chen L. Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol. 2011;187:1537–41.CrossRefGoogle Scholar
  76. 76.
    Yoon KW, Byun S, Kwon E, Hwang S-Y, Chu K, Hiraki M, et al. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science. 2015;349:1261669.CrossRefGoogle Scholar
  77. 77.
    Rosenzweig M, Molloy M, Guo Y, Rothstein J. Identification of Vsig8 as the putative Vista receptor and its use thereof to produce Vista/Vsig8 modulators [Internet]. 2016. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016090347. Cited 15 Jun 2018.
  78. 78.
    Wang J, Wu G, Manick B, Hernandez V, Renelt M, Bi M, et al. VSIG-3/IGSF11 is a ligand of VISTA/PD-1H and inhibits human T cell function. J Immunol. 2017;198:154.1.Google Scholar
  79. 79.
    Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, et al. Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer. Clin Cancer Res. 2018;24:1562–73.CrossRefGoogle Scholar
  80. 80.
    Böger C, Behrens H-M, Krüger S, Röcken C. The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: a future perspective for a combined gastric cancer therapy? Oncoimmunology. 2017;6:e1293215.CrossRefGoogle Scholar
  81. 81.
    Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, et al. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol. 2017;30:1666–76.CrossRefGoogle Scholar
  82. 82.
    A study of safety, pharmacokinetics, pharmacodynamics of JNJ-61610588 in participants with advanced cancer—full text view—ClinicalTrials.gov [Internet].https://clinicaltrials.gov/ct2/show/NCT02671955. Cited 6 May 2018.
  83. 83.
    Spaller M, Noelle R, Ceeraz S, Lemercier I, Nowak E, Lines J, et al. Vista antagonist and methods of use [Internet]. 2015. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015109340. Cited 6 May 2018.
  84. 84.
    Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. Vista signaling pathway inhibitory compounds useful as immunomodulators [Internet]. 2018. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018047143&redirectedID=true. Cited 6 May 2018.
  85. 85.
    Sasikumar PG, Naremaddepalli SS, Ramachandra RK, Gowda N, Yerramsetti MR, Bandireddy SR, et al. Abstract B006: functional antagonism of VSIG8-mediated immune suppression by oral VISTA agents. Mol Cancer Ther. 2018;17:B006.Google Scholar
  86. 86.
    Edris B, Weiskopf K, Volkmer AK, Volkmer J-P, Willingham SB, Contreras-Trujillo H, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci USA. 2012;109:6656–61.CrossRefGoogle Scholar
  87. 87.
    Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.CrossRefGoogle Scholar
  88. 88.
    Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142:699–713.CrossRefGoogle Scholar
  89. 89.
    Petrova PS, Viller NN, Wong M, Pang X, Lin GHY, Dodge K, et al. TTI-621 (SIRPαFc): a CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clin Cancer Res. 2017;23:1068–79.CrossRefGoogle Scholar
  90. 90.
    Ring NG, Herndler-Brandstetter D, Weiskopf K, Shan L, Volkmer J-P, George BM, et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc Natl Acad Sci USA. 2017;114:E10578–85.CrossRefGoogle Scholar
  91. 91.
    Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, et al. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med. 2017;9:eaaf2968.  https://doi.org/10.1126/scitranslmed.aaf2968 CrossRefPubMedGoogle Scholar
  92. 92.
    Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10:e0137345.CrossRefGoogle Scholar
  93. 93.
    Hu5F9-G4 monotherapy or Hu5F9-G4 in combination with azacitidine in patients with hematological malignancies—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT03248479. Cited 15 Jun 2018.
  94. 94.
    A phase 1, dose finding study of CC-90002 in subjects with advanced solid and hematologic cancers—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02367196. Cited 15 Jun 2018.
  95. 95.
    A trial of TTI-621 for patients with hematologic malignancies and selected solid tumors—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02663518. Cited 15 Jun 2018.
  96. 96.
    Study of SRF231 in patients with advanced solid and hematologic cancers—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT03512340. Cited 15 Jun 2018.
  97. 97.
    A study of ALX148 in patients with advanced solid tumors and lymphoma—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT03013218. Cited 15 Jun 2018.
  98. 98.
    Ansell SM, Chen RW, Flinn I, Maris MB, O’Connor OA, Wieland E, et al. A phase 1 study of TTI-621, a novel immune checkpoint inhibitor targeting CD47, in subjects with relapsed or refractory hematologic malignancies. JCO. 2016;34:TPS7585.CrossRefGoogle Scholar
  99. 99.
    Sikic BI, Narayanan S, Colevas AD, Padda SK, Fisher GA, Supan D, et al. A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. JCO. 2016;34:3019.CrossRefGoogle Scholar
  100. 100.
    Advani R, Flinn I, Popplewell L, Forero-Torres A. Activity and tolerabilty of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: initial phase 1b/2 results. J Clin Oncol. 2018;36(suppl; abstr 7504).CrossRefGoogle Scholar
  101. 101.
    Sasikumar PG, Gundala C, Gowda NM, Naremaddepalli SS, Bhumireddy A, Nair R, et al. Abstract 1650: targeting CD47- SIRPα interaction by novel peptide-based antagonists. Cancer Res. 2017;77:1650.CrossRefGoogle Scholar
  102. 102.
    Sasikumar PG, Gundala C, Balasubramanian WR, Naremaddepalli SS, Bhumireddy A, Patil SS, et al. Abstract B007: potent antitumor activity of a novel and orally available small-molecule antagonist targeting the CD47/SIRPα pathway. Mol Cancer Ther. 2018;17:B007.Google Scholar
  103. 103.
    Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014;35:51–60.CrossRefGoogle Scholar
  104. 104.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.CrossRefGoogle Scholar
  105. 105.
    A study of CA-170 (Oral PD-L1, PD-L2 and VISTA checkpoint antagonist) in patients with advanced tumors and lymphomas—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02812875. Cited 19 Jun 2018.
  106. 106.
    Lazorchak AS, Patterson T, Ding Y, Sasikumar PG, Sudarshan NS, Gowda NM, et al. Abstract A36: CA-170, an oral small molecule PD-L1 and VISTA immune checkpoint antagonist, promotes T cell immune activation and inhibits tumor growth in pre-clinical models of cancer. Cancer Immunol Res. 2017;5:A36.CrossRefGoogle Scholar
  107. 107.
    Powderly J, Patel MR, Lee JJ, Brody J, Meric-Bernstam F, Hamilton E, et al. 1141PDCA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study. Ann Oncol [Internet]. 2017;28. https://academic.oup.com/annonc/article/28/suppl_5/mdx376.007/4109221. Cited 19 Jun 2018.
  108. 108.
    Hughes JD, Blagg J, Price DA, Bailey S, Decrescenzo GA, Devraj RV, et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett. 2008;18:4872–5.CrossRefGoogle Scholar
  109. 109.
    Valko K, Chiarparin E, Nunhuck S, Montanari D. In vitro measurement of drug efficiency index to aid early lead optimization. J Pharm Sci. 2012;101:4155–69.CrossRefGoogle Scholar
  110. 110.
    Higueruelo AP, Schreyer A, Bickerton GRJ, Blundell TL, Pitt WR. What can we learn from the evolution of protein-ligand interactions to aid the design of new therapeutics? PLoS One [Internet]. 2012;7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519888/. Cited 12 Aug 2018.

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Aurigene Discovery Technologies LimitedBangaloreIndia

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