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Insight ISSUE 1 ISSUE 1 IMMUNE CHECKPOINTS & insight IMMUNOTHERAPY RESEARCH Immune Checkpoints and Cancer Cancer immunotherapy seeks to use the many A better approach is to intervene when T cells components of the immune system to attack meet cancer cells, where TCR-mediated activation cancer cells. More specifically, immunotherapy initiates cell killing. Programmed death-1 (PD-1) is maximizes the effectiveness of components of a lymphocyte receptor that binds PD-L1 or PD-L2. the antigen-presentation and antigen-response When PD-L1 is expressed on cancer cells, it causes system, primarily dendritic cells and lymphocytes, PD-1 to negatively regulate TCR-mediated activation respectively. Ideally, this approach can offer more of T cells, limiting their cytotoxic activity. Several selective killing of cancer cells than other therapeutic antibodies have been developed to block the modalities, such as chemotherapy. ability of PD-L1 to interact with PD-1. Clinical trials using these antibodies to antagonize the PD-L1/PD-1 Immune checkpoint therapy is a form of cancer interaction have demonstrated tumor killing that is immunotherapy that centers on lymphocyte both specific and long-lasting.3,4 In May 2016, signaling, with a current focus on T cells. These the first PD-L1 inhibitor was approved by the cells can be activated to multiply, secrete cytokines, U.S. Food and Drug Administration for the and kill target cells with high selectivity. Activation treatment of bladder cancer. requires the T cell receptor (TCR) be stimulated by an antigen presented by the major histocompatibility Studies using antibodies to block the inhibitory complex (Ag/MHC). Selectivity and strength of checkpoint receptors CTLA-4 and PD-1 demonstrate activation are regulated by co-stimulatory or the feasibility of this type of immunotherapy. Of inhibitory signals, the immune checkpoints. course, antibody blockade of PD-1 will only be effective when cancer cells express ligands that The goal of immune checkpoint therapy is to stimulate PD-1. Other cancer cells may use different enhance the ability of T cells to kill cancer cells, ligands to suppress the immune system. With this primarily by tweaking the regulatory checkpoints in mind, additional inhibitory checkpoints are being on T cells. The best-studied examples are identified (Table 1), and approaches targeting co-receptors that suppress TCR-mediated activation checkpoint activation can also be considered.1,5 of T cells. CTL-associated protein-4 (CTLA-4) is an inhibitory co-receptor on T cells that, when stimulated In addition to signaling through surface membrane at the same time as TCR, blocks cell activation. checkpoint proteins, effective therapies target Antibodies selective for CTLA-4 prevent its immunosuppression through metabolic pathways, stimulation, allowing TCR-mediated T cell activation. such as indoleamine dioxygenases (IDOs) and While this approach has shown some effectiveness arginase, as well as through soluble signaling factors in treating cancer in patients, the response is slow (e.g., TGF-β, adenosine).6 These may be best and not always selective for cancer cells.1,2 One targeted using traditional small molecule inhibitors. major problem is that CTLA-4 blockade works early Combination therapies using both antibodies and in T cell development, when antigen-presenting inhibitors will be a central part of cancer treatment cells are activating T cells to proliferate. in the future. References 1. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252-264 (2012). 2. Farkona, S., Diamandis, E.P., and Blasutig, I.M. Cancer immunotherapy: The beginning of the end of cancer? BMC Med. 14(1), (2016). 3. Chen, D.S. and Mellman, I. Oncology meets immunology: The cancer-immunity cycle. Immunity 39(1), 1-10 (2013). 4. Norde, W.J., Hobo, W., van der Voort, R., et al. Coinhibitory molecules in hematologic malignancies: Targets for therapeutic intervention. Blood 120(4), 728-736 (2016). 5. Collin, M. Immune checkpoint inhibitors: A patent review (2010-2015). Expert Opin. Ther. Pat. 26(5), 555-564 (2016). 6. Antonia, S.J., Vansteenkiste, J.F., and Moon, E. Immunotherapy: Beyond anti-PD-1 and anti-PD-L1 therapies. Am. Soc. Clin. Oncol. Educ. Book 35, e450-e458 (2016). Tel. 0800-246 66 51 · Fax 0800-246 66 52 All products are for laboratory research use only: 2 [email protected] · www.biomol.de · www.biomol.com Not for administration to humans. DENDRITIC T CELL T CELL CANCER CELL CELL MHC Ag TCR ACTIVATION ACTIVATION (PROLIFERATION) (KILLING) TCR Ag MHC B7 CD28 PD-1 PD-L1 B7 CTLA-4 MIGRATION THERAPEUTIC BLOCKADE THERAPEUTIC BLOCKADE Figure. Co-stimulation of TCR and CD28 on T cells by Ag/MHC and B7 on dendritic cells activates T cells to proliferate and migrate. Negative regulation of TCR by B7:CTLA-4 signaling can be blocked by therapeutic antibodies. Similarly, signaling from Ag/MHC on cancer cells, through TCR, activates killing of cancer cells by T cells. Inhibition of this activation by PD-L1:PD-1 is another target of therapeutic blockade. Antigen Presenting Cell T Cell Antigen Presenting Cell T Cell Ligand/Receptor Ligand/Receptor Ligand/Receptor Ligand/Receptor Also known as Also known as Also known as Also known as CD40 CD40L KIR TNFRSF5 TNFSF5, CD154 TCR TL1A DR3 MHC Class I, II TL1A, TNFSF15 TNFRSF25 LAG3 GITRL GITR CD223 TNFSF18 TNFRSF18, CD357 CD80 4-1BBL 4-1BB B7-1 CTLA-4 TNFSF9, CD137L TNFRSF9, CD137 CD86 CD152 OX40L OX40 B7-2 TNFSF4, CD252 TNFRSF4, CD134 CD80 PD-L1 CD70 CD27 B7-1 B7-H1, CD274 TNFSF7, CD27L TNFRSF7 PD-L1 B7-H1, CD274 HHLA2 TMIGD2 PD-1 PD-L2 CD279 ICOSL ICOS B7-DC, CD273 B7-H2, CD275 CD278 PD-L1 CD80 CD80 B7-H1, CD274 B7-1 B7-1 CD28 VISTA (2) N/A CD86 B7-2 BTNL2 (2) N/A B7-H3 N/A Table 1. Ligand-receptor pairings relevant to immune checkpoint therapy. CD276 Pairings that evoke inhibitory signaling are shaded red, while co-stimulatory B7-H4 N/A pairings are shaded green. (Adapted from Mahoney, K.M., Rennert, P.D., VTCN1 Freeman, G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14(8), 561-584 (2015)) CD48 N/A Phosphatidylserine TIM-3 (2) Gal9 HAVcr-2 BTLA CD272 HVEM CD160 TNFRSF14, CD270 LIGHT TNFSF14, HVEML All products are for laboratory research use only: Tel. 0800-246 66 51 · Fax 0800-246 66 52 Not for administration to humans. [email protected] · www.biomol.de · www.biomol.com 3 Antibodies Antibodies to Detect Immune Checkpoint Proteins Catalog No. Product Name Cross Reactivity Available Conjugate(s) Application(s) Anti-Adenosine Receptor A2A Polyclonal ARG55154 Human FC, IHC, WB Antibody ARG64303 Anti- B7- H4 Polyclonal Antibody Human WB ARG55418 Anti- BTLA / CD272 Polyclonal Antibody Human IHC, WB ARG55520 Anti- BTLA / CD272 Polyclonal Antibody Mouse, Rat WB Anti-CD27 Monoclonal Antibody ARG62793 Human APC, FITC, PE FC (Clone LT27) Anti-CD28 Monoclonal Antibody APC, Biotin, FITC, PE, Spectral ARG20895 Mouse FC, IP (Clone PV-1) Red Anti-CD28 Monoclonal Antibody ARG65430 Human, Primate APC, FITC, PE, PerCP FA, FC, ICC, IF, IHC, IP, WB (Clone CD28.2) Anti-CD28 Monoclonal Antibody ARG65471 Rat FITC, PE FA, FC, IP (Clone JJ319) Anti- CD28 Monoclonal Antibody, ARG62796 Mouse FA, FC, ICC, IF, IHC, IP Functional Grade (Clone 37.51) ARG65637 Anti-CD28 Polyclonal Antibody Mouse WB ARG65638 Anti-CD28 Polyclonal Antibody Human WB ARG52770 Anti-CD40 Polyclonal Antibody Human IHC Anti-CD40 Monoclonal Antibody APC, Biotin, FITC, PE, Spectral ARG20924 Mouse BL, FA, FC, IP (Clone 1C10) Red Anti-CD40 Monoclonal Antibody ARG62838 Human FITC, PE, PerCP FC (Clone HI40a) Anti- CD40L Monoclonal Antibody ARG65514 Mouse FITC FA, FC, ICC, IF, IHC, IP (Clone MR- 1) ARG65039 Anti-CD80 Internal Polyclonal Antibody Human WB Anti-CD80 Monoclonal Antibody APC, Biotin, FITC, PE, Spectral ARG20951 Mouse BL, FC, IP (Clone 1G10) Red Anti-CD80 Monoclonal Antibody ARG62932 Dog, Mouse FA, FC, IHC, IP (Clone 16-10A1) Anti-CD80 Monoclonal Antibody ARG62931 Human APC, FITC, PE, PerCP FC, IP (Clone MEM-233) Anti-CD86 Monoclonal Antibody APC, Biotin, FITC, PE, PE-Cy7, ARG21088 Mouse BL, ELISA, FC, IHC, IP (Clone 2D10) Spectral Red Anti-CD86 Monoclonal Antibody ARG65423 Human APC, FITC, PE, PerCP FA, FC, IHC, IP, WB (Clone BU63) Anti-CD86 Monoclonal Antibody ARG62938 Mouse FITC FA, FC, ICC, IF, IHC, IP (Clone GL-1) Anti- CD152 / CTLA4 Monoclonal ARG21001 Mouse Biotin, FITC, PE ELISA, FC Antibody (Clone 1B8) Anti- CD152 / CTLA4 Monoclonal ARG65419 Human PE FC, ICC, IF, IHC, IP Antibody (Clone BNI3) Tel. 0800-246 66 51 · Fax 0800-246 66 52 All products are for laboratory research use only: 4 [email protected] · www.biomol.de · www.biomol.com Not for administration to humans. Catalog No. Product Name Cross Reactivity Available Conjugate(s) Application(s) Anti-HVEM / TR2 Polyclonal Antibody, ARG63868 Human WB Internal ARG63890 Anti- INDO / IDO Polyclonal Antibody Human IHC ARG64972 Anti-INDOL1 Polyclonal Antibody Human WB ARG63796 Anti- PDCD1 Polyclonal Antibody, Internal Human WB ARG63715 Anti- PD- L1 Polyclonal Antibody Human IHC, WB ARG54798 Anti- TIM-3 Polyclonal Antibody Human, Mouse WB Catalog No. Product Name Cross Reactivity Available Conjugate(s) Application(s) Anti-CTLA4 Neutralizing BPS-71212 Human Neutr. Monoclonal Antibody Anti-PD-1 Neutralizing BPS-71120 Human, Monkey Neutr. Monoclonal Antibody Anti-PD-1 Neutralizing Monoclonal BPS-71290 Human, Monkey PE FC, IF Antibody, PE-labeled Anti-PD-L1 Neutralizing BPS-71213 Human, Mouse Neutr. Monoclonal Antibody Anti-PD-L1 Neutralizing Monoclonal BPS-71214 Human, Mouse Biotin ELISA, WB Antibody,
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