Top

Published in:

01-09-2019 | Original Article

A VEGFR2–MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice

Authors: Yao Xu, Xinrong Zhang, Yong Wang, Mingzhu Pan, Min Wang, Juan Zhang

Published in: Cancer Immunology, Immunotherapy | Issue 9/2019

Abstract

MHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2–MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis by blocking the VEGFR2 signaling pathway. Additionally, JZC01 promoted NK and CD8⁺ T cells to release IFN-γ and engaged activated lymphocytes to lysis of VEGFR2-expressing tumor cells. The in vivo anti-tumor activity of JZC01 was investigated by establishing a Lewis lung cancer cell-transplanted mouse model. It effectively reduced the tumor vascular density and increased the infiltration and activation of NK and CD8⁺ T cells in the tumor microenvironment. Thus, JZC01 functions in anti-tumor angiogenesis and anti-tumor immune activation, and showed improved anti-tumor efficacy combined with docetaxel, which provides a new insight into anti-tumor therapy.

Available only for authorised users

Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723. https://doi.org/10.1016/j.cell.2017.01.017 CrossRefPubMedPubMedCentral

Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, Stevanovic S, Rammensee HG, Steinle A (2008) Tumor-associated MICA is shed by ADAM proteases. Can Res 68(15):6368–6376CrossRef

Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441. https://doi.org/10.1146/annurev-immunol-032712-095951 CrossRefPubMedPubMedCentral

Gasser S, Orsulic S, Brown EJ, Raulet DH (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436(7054):1186–1190. https://doi.org/10.1038/nature03884 CrossRefPubMedPubMedCentral

Spear P, Wu MR, Sentman ML, Sentman CL (2013) NKG2D ligands as therapeutic targets. Cancer Immun 13(2):8PubMedPubMedCentral

Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T (2001) Costimulation of CD8 alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2(3):255–260. https://doi.org/10.1038/85321 CrossRefPubMed

Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285(5428):727–729CrossRefPubMed

Hu J, Batth IS, Xia X, Li S (2016) Regulation of NKG2D⁺CD8⁺ T-cell-mediated antitumor immune surveillance: identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism. Oncoimmunology 5(12):e1252012. https://doi.org/10.1080/2162402X.2016.1252012 CrossRefPubMedPubMedCentral

Kaiser BK, Yim D, Chow IT, Gonzalez S, Dai Z, Mann HH, Strong RK, Groh V, Spies T (2007) Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 447(7143):482–486. https://doi.org/10.1038/nature05768 CrossRefPubMed

10.

Boutet P, Aguera-Gonzalez S, Atkinson S, Pennington CJ, Edwards DR, Murphy G, Reyburn HT, Vales-Gomez M (2009) Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol 182(1):49–53CrossRefPubMed

11.

Raffaghello L, Prigione I, Airoldi I, Camoriano M, Levreri I, Gambini C, Pende D, Steinle A, Ferrone S, Pistoia V (2004) Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia 6(5):558–568CrossRefPubMedPubMedCentral

12.

Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J, Neuberg D, Anderson KC, Carrasco DR, Dranoff G (2008) MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA 105(4):1285–1290. https://doi.org/10.1073/pnas.0711293105 CrossRefPubMedPubMedCentral

13.

Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR (2006) Soluble MICA in malignant diseases. Int J Cancer 118(3):684–687. https://doi.org/10.1002/ijc.21382 CrossRefPubMed

14.

Huergo-Zapico L, Gonzalez-Rodriguez AP, Contesti J, Gonzalez E, Lopez-Soto A, Fernandez-Guizan A, Acebes-Huerta A, de Los Toyos JR, Lopez-Larrea C, Groh V et al (2012) Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding. Cancer Immunol Immunother 61(8):1201–1210. https://doi.org/10.1007/s00262-011-1195-z CrossRefPubMed

15.

Jia HY, Liu JL, Zhou CJ, Kong F, Yuan MZ, Sun WD, Wang J, Liu L, Zhao JJ, Luan Y (2014) High expression of MICA in human kidney cancer tissue and renal cell carcinoma lines. Asian Pac J Cancer Prev 15(4):1715–1717CrossRefPubMed

16.

Liu Y, Guo X, Xing M, Zhao K, Luo L, Du J (2018) Prognostic value of serum levels of soluble MICA (sMICA) in patients with prostate cancer. Br J Biomed Sci 75(2):98–100. https://doi.org/10.1080/09674845.2017.1402405 CrossRefPubMed

17.

Cascone R, Carlucci A, Pierdiluca M, Santini M, Fiorelli A (2017) Prognostic value of soluble major histocompatibility complex class I polypeptide-related sequence A in non-small-cell lung cancer—significance and development. Lung Cancer (Auckl) 8:161–167. https://doi.org/10.2147/LCTT.S105623 CrossRef

18.

Xing S, Zhu Y, Sun Y (2017) Serum smica as biomarker in detection of non-small-cell lung carcinoma. Br J Biomed Sci 2017:1–3

19.

Wang LP, Niu H, Xia YF et al (2015) Prognostic significance of serum sMICA levels in non-small cell lung cancer. Eur Rev Med Pharmacol Sci 19(12):2226PubMed

20.

Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419(6908):734–738. https://doi.org/10.1038/nature01112 CrossRefPubMed

21.

Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet 388(10043):518–529. https://doi.org/10.1016/S0140-6736(15)01088-0 CrossRefPubMed

22.

Maishi N, Hida K (2017) Tumor endothelial cells accelerate tumor metastasis. Cancer Sci 108(10):1921–1926. https://doi.org/10.1111/cas.13336 CrossRefPubMedPubMedCentral

23.

Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, Mackey JR, Paz-Ares L, Baron AD, Okusaka T et al (2017) Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol 28(12):2932–2942. https://doi.org/10.1093/annonc/mdx514 CrossRefPubMedPubMedCentral

24.

Sitohy B, Nagy JA, Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72(8):1909–1914. https://doi.org/10.1158/0008-5472.CAN-11-3406 CrossRefPubMedPubMedCentral

25.

Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370. https://doi.org/10.1038/nm.2537 CrossRefPubMed

26.

Jung K, Heishi T, Khan OF, Kowalski PS, Fukumura D (2017) Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest 127(8):3039–3051. https://doi.org/10.1172/JCI93182 CrossRefPubMedPubMedCentral

27.

Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G (2015) Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep 11(4):577–591. https://doi.org/10.1016/j.celrep.2015.03.055 CrossRefPubMedPubMedCentral

28.

Shrimali RK et al (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180CrossRefPubMedPubMedCentral

29.

Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F et al (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA 109(43):17561–17566. https://doi.org/10.1073/pnas.1215397109 CrossRefPubMedPubMedCentral

30.

Zhang J, Li H, Wang X, Qi H, Miao X, Zhang T, Chen G, Wang M (2012) Phage-derived fully human antibody scFv fragment directed against human vascular endothelial growth factor receptor 2 blocked its interaction with VEGF. Biotechnol Prog 28(4):981–989. https://doi.org/10.1002/btpr.1559 CrossRefPubMed

31.

Xie W, Li D, Zhang J, Li Z, Acheampong DO, He Y, Wang Y, Chen Z, Wang M (2014) Generation and characterization of a novel human IgG1 antibody against vascular endothelial growth factor receptor 2. Cancer Immunol Immunother 63(9):877–888. https://doi.org/10.1007/s00262-014-1560-9 CrossRefPubMed

32.

Acheampong DO, Tang M, Wang Y, Zhao X, Xie W, Chen Z et al (2017) A novel fusion antibody exhibits antiangiogenic activity and stimulates NK cell-mediated immune surveillance through fused NKG2D ligand. J Immunother 40(3):94–103. https://doi.org/10.1097/CJI.0000000000000157 CrossRefPubMed

33.

Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF Jr, Harvey CJ et al (2018) Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359(6383):1537–1542. https://doi.org/10.1126/science.aao0505 CrossRefPubMedPubMedCentral

34.

Wang T, Sun F, Xie W, Tang M, He H, Jia X, Tian X, Wang M, Zhang J (2016) A bispecific protein rG7S-MICA recruits natural killer cells and enhances NKG2D-mediated immunosurveillance against hepatocellular carcinoma. Cancer Lett 372(2):166–178. https://doi.org/10.1016/j.canlet.2016.01.001 CrossRefPubMed

35.

Stoufer LK, Davies LD, Culpepper D, McFarland BJ (2009) Rational design of enhanced affinity at the MICA-NKG2D interface (134.51). J Immunol 182:134.151–134.151

36.

Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, Zeng W, Giobbie-Hurder A, Atkins MB, Ibrahim N et al (2014) Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2(7):632–642. https://doi.org/10.1158/2326-6066.CIR-14-0053 CrossRefPubMedPubMedCentral

37.

Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS et al (2016) Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 7:12624. https://doi.org/10.1038/ncomms12624 CrossRefPubMedPubMedCentral

38.

Ramjiawan RR, Griffioen AW, Duda DG (2017) Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis 20(2):185–204. https://doi.org/10.1007/s10456-017-9552-y CrossRefPubMedPubMedCentral

39.

Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B et al (2009) Nk cell-mediated killing of target cells triggers robust antigen-specific T cell-mediated and humoral responses. Blood 113(26):6593–6602CrossRefPubMedPubMedCentral

40.

Deng J, Liu X, Rong L, Ni C, Li X, Yang W (2014) Ifnγ-responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down-regulation of dll4. J Pathol 233(2):170–182CrossRefPubMed

41.

Lu Y, Yang W, Qin C, Zhang L, Deng J, Liu S et al (2009) Responsiveness of stromal fibroblasts to ifn-γ blocks tumor growth via angiostasis. J Immunol 183(10):6413–6421CrossRefPubMed

42.

Khan KA, Kerbel RS (2018) Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15:310–324CrossRefPubMed

Title: A VEGFR2–MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice
Authors: Yao Xu
Xinrong Zhang
Yong Wang
Mingzhu Pan
Min Wang
Juan Zhang
Publication date: 01-09-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 9/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02379-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2019

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone

Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature

Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells

Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer