Fibroblast Activation Protein α-Targeted CD40 Agonism Abrogates Systemic Toxicity and Enables Administration of High Doses to Induce Effective Antitumor Immunity.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
received:
11
12
2020
revised:
12
02
2021
accepted:
24
03
2021
pubmed:
28
3
2021
medline:
1
4
2022
entrez:
27
3
2021
Statut:
ppublish
Résumé
CD40 agonists hold great promise for cancer immunotherapy (CIT) as they enhance dendritic cell (DC) activation and concomitant tumor-specific T-cell priming. However, the broad expression of CD40 accounts for sink and side effects, hampering the efficacy of anti-CD40 antibodies. We hypothesized that these limitations can be overcome by selectively targeting CD40 agonism to the tumor. Therefore, we developed a bispecific FAP-CD40 antibody, which induces CD40 stimulation solely in presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma. FAP-CD40's FAP-CD40 triggered a potent, strictly FAP-dependent CD40 stimulation FAP-CD40 abrogates the systemic toxicity associated with nontargeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing antitumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT.
Identifiants
pubmed: 33771854
pii: 1078-0432.CCR-20-4001
doi: 10.1158/1078-0432.CCR-20-4001
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CD40 Antigens
0
Membrane Proteins
0
Endopeptidases
EC 3.4.-
fibroblast activation protein alpha
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4036-4053Informations de copyright
©2021 American Association for Cancer Research.
Références
Dadgostar H, Zarnegar B, Hoffmann A, Qin XF, Truong U, Rao G, et al. Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes. Proc Natl Acad Sci U S A. 2002;99:1497–502.
Gallagher E, Enzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol. 2007;8:57–63.
van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67:2–17.
Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol. 2004;22:307–28.
French RR, Chan HT, Tutt AL, Glennie MJ. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med. 1999;5:548–53.
Sotomayor EM, Borrello I, Tubb E, Rattis FM, Bien H, Lu Z, et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med. 1999;5:780–7.
Vonderheide RH. CD40 agonist agntibodies in cancer immunotherapy. Annu Rev Med. 2020;71:47–58.
Vonderheide RH. The immune revolution: a case for priming, not checkpoint. Cancer Cell. 2018;33:563–9.
Morrison AH, Diamond MS, Hay CA, Byrne KT, Vonderheide RH. Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity. Proc Natl Acad Sci U S A. 2020;117:8022–31.
Grilley-Olson JE, Curti BD, Smith DC, Goel S, Gajewski T, Markovic S, et al. SEA-CD40, a non-fucosylated CD40 agonist: interim results from a phase 1 study in advanced solid tumors. J Clin Oncol. 2018;36:3093.
Bendell JC, Fakih M, Infante JR, Bajor DL, Cristea MC, Tremblay T, et al. Phase 1 study to evaluate the safety and tolerability of the CD40 agonistic monoclonal antibody APX005M in subjects with solid tumors. J Clin Oncol. 2016;34:TPS3110–TPS.
Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25:876–83.
Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Shankles B, et al. SGN-40 (Anti-huCD40 mAb) monotherapy induces durable objective responses in patients with relapsed aggressive non-Hodgkin's lymphoma: evidence of antitumor activity from a phase I study. Blood. 2006;108:695.
Ruter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther. 2010;10:983–93.
Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013;2:e23033.
Fransen MF, Sluijter M, Morreau H, Arens R, Melief CJ. Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin Cancer Res. 2011;17:2270–80.
Knorr DA, Dahan R, Ravetch JV. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A. 2018;115:11048–53.
Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A. 1990;87:7235–9.
Rettig WJ, Garin-Chesa P, Beresford HR, Oettgen HF, Melamed MR, Old LJ. Cell-surface glycoproteins of human sarcomas: differential expression in normal and malignant tissues and cultured cells. Proc Natl Acad Sci U S A. 1988;85:3110–4.
Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc Natl Acad Sci U S A. 2014;111:12139–44.
Jansen CS, Prokhnevska N, Master VA, Sanda MG, Carlisle JW, Bilen MA, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature. 2019;576:465–70.
Hunter TB, Alsarraj M, Gladue RP, Bedian V, Antonia SJ. An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model. Scand J Immunol. 2007;65:479–86.
Schlothauer T, Herter S, Koller CF, Grau-Richards S, Steinhart V, Spick C, et al. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng Des Sel. 2016;29:457–66.
Carter P. Bispecific human IgG by design. J Immunol Methods. 2001;248:7–15.
Schaefer W, Regula JT, Bahner M, Schanzer J, Croasdale R, Durr H, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A. 2011;108:11187–92.
Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, et al. Tumor-targeted 4–1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019;11:eaav5989.
Kelley SK, Gelzleichter T, Xie D, Lee WP, Darbonne WC, Qureshi F, et al. Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. Br J Pharmacol. 2006;148:1116–23.
Rolink A, Melchers F, Andersson J. The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching. Immunity. 1996;5:319–30.
Mizobata S, Tompkins K, Simpson JF, Shyr Y, Primus FJ. Induction of cytotoxic T cells and their antitumor activity in mice transgenic for carcinoembryonic antigen. Cancer Immunol Immunother. 2000;49:285–95.
Lo A, Wang LS, Scholler J, Monslow J, Avery D, Newick K, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800–10.
Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC, Chan R, et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J Biol Chem. 2016;291:5986–96.
Clarke P, Mann J, Simpson JF, Rickard-Dickson K, Primus FJ. Mice transgenic for human carcinoembryonic antigen as a model for immunotherapy. Cancer Res. 1998;58:1469–77.
Fletcher AL, Malhotra D, Acton SE, Lukacs-Kornek V, Bellemare-Pelletier A, Curry M, et al. Reproducible isolation of lymph node stromal cells reveals site-dependent differences in fibroblastic reticular cells. Front Immunol. 2011;2:35.
Richman LP, Vonderheide RH. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol Res. 2014;2:19–26.
Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333:1030–4.
Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med. 2002;196:1627–38.
Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. T cell receptor antagonist peptides induce positive selection. Cell. 1994;76:17–27.
Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35.
Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell. 2018;172:1022–37.
White AL, Chan HT, French RR, Willoughby J, Mockridge CI, Roghanian A, et al. Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. Cancer Cell. 2015;27:138–48.
Yu X, Chan HTC, Fisher H, Penfold CA, Kim J, Inzhelevskaya T, et al. Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity. Cancer Cell. 2020;37:850–66.
Stewart R, Hammond SA, Oberst M, Wilkinson RW. The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer. J Immunother Cancer. 2014;2:29.
Paul WE. Fundamental immunology. 2008.
White AL, Chan HT, Roghanian A, French RR, Mockridge CI, Tutt AL, et al. Interaction with FcgammaRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J Immunol. 2011;187:1754–63.
Labiano S, Roh V, Godfroid C, Hiou-Feige A, Romero J, Sum E, et al. CD40 agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine HPV-positive head and neck tumors. Clin Cancer Res. 2021.
Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30:324–36.
Acton SE, Astarita JL, Malhotra D, Lukacs-Kornek V, Franz B, Hess PR, et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity. 2012;37:276–89.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.
Hoves S, Ooi CH, Wolter C, Sade H, Bissinger S, Schmittnaegel M, et al. Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J Exp Med. 2018;215:859–76.
Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL. IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6:400–13.
O Hara MH, O Reilly E, Rosemarie M, Varadhachary G, Wainberg Z, Ko A, et al. Abstract CT004: A phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients. Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29–Apr 3; Atlanta, GA. 2019.
Yasmin-Karim S, Bruck PT, Moreau M, Kunjachan S, Chen GZ, Kumar R, et al. Radiation and local anti-CD40 generate an effective in situ vaccine in preclinical models of pancreatic cancer. Front Immunol. 2018;9:2030.