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9 Gopal, AK, Kahl, BS, de Vos, S et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008- 1018. 10 Evans, TRJ, Italiano, A, Eskens, F et al. Phase 1-2 study of TI-061 alone and in combination with other anti- cancer agents in patients with advanced malignancies. J Clin Oncol 2017; 35: TPS3109- TPS3109. 11 Holland, PM, Normant, E, Adam, A et al. CD47 Monoclonal Antibody SRF231 Is a Potent Inducer of Macrophage-Mediated Tumor Cell Phagocytosis and Reduces Tumor Burden in Murine Models of Hematologic Malignancies. Blood 2016; 128: 1843-1843. 12 https://www.fortyseveninc. com/application/files/5415/438 7/4524/ASH_2018_- _Forty_Seven_Poster_RBC_Pr uning_FINAL.pdf. 13 Petrova, PS, Viller, NN, Wong, M et al. TTI-621 (SIRPalphaFc): A CD47- Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding. Clin Cancer Res 2017; 23: 1068-1079. 14 Uger, RA. Targeting the CD47 “Do Not Eat” Signal with TTI-621 (SIRP-IgG1 Fc). In 16th Annual Discovery on Target Conference. Boston, MA: 2018. 15 Querfeld, C, Thompson, JA, Taylor, M et al. Intralesional Injection of the CD47-blocking immune checkpoint inhibitor TTI-621 (SIRPFc) induces antitumor activity in patients with relapsed/refractory mycosis fungoides and Sezary syndrome: Interim results of a multicenter Phase 1 trial. European Journal of Cancer 2018; 101: S34. 16 Kauder, SE, Kuo, TC, Harrabi, O et al. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. PLoS One 2018;

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system catches up with our knowledge of adaptive immune responses – and how the two work togeth- er – several modulators of the innate immune sys- tem are being advanced. These include toll-like receptor (TLR) agonists, which can activate innate immune cells, therefore causing them to secrete cytokines and interferons and, subsequently, recruit and activate adaptive T- and B-cells. However, such agents tend to be toxic when given systemically. Currently, TLR agonists are delivered locally via intratumoral injection and other strate- gies to target them specifically to tumours are being explored. Other innate immune modulators, such as NK

cell activators and checkpoint inhibitors, and macrophage checkpoint inhibitors, stimulate innate immune cells to attack cancer cells directly and activate adaptive immune responses. In the clinic already are macrophage checkpoint inhibitors that target CD47, a protein expressed by most cells in the body that binds with SIRP on the surface of macrophages. It is a powerful ‘don’t eat me’ signal that helps macrophages identify host cells as healthy cells, preventing phagocytosis. In normal physiology, macrophages detect the

balance of CD47 ‘don’t eat me’ signals present on a cell membrane against ‘eat me’ signals indicating the cell is diseased or distressed. Phagocytosis is triggered when the ‘eat me’ signals overwhelm the ‘don’t eat me’ signals. This is one way damaged and diseased host cells are detected and removed, and is the typical mechanism for removing older red blood cells from circulation. Similarly, most invading organisms do not express CD47, enabling macrophages to immediately recognise foreign cells and attack. However, many cancers, both solid and hemato-

logical, over-express CD47. This prevents macrophages from attacking cancer cells, even though they also display several surface proteins indicating distress. It is as though the over- expressed CD47 acts as a bright light, blinding the macrophage to the presence of ‘eat me’ distress signals. Blocking CD47 on cancer cells with monoclonal

antibodies allows macrophages to respond normal- ly to the ‘eat me’ proteins that are also present on cancer cells, triggering phagocytosis. This process can be enhanced by supplying an additional ‘eat me’ signal through a tumour-targeted antibody such as rituximab. In addition to directly destroy- ing cells by phagocytosis, macrophages and den- dritic cells then present peptide antigens from the digested cancer cells to the adaptive immune sys- tem, activating T-cells against these tumour-specif-

ic antigens wherever they may be found in the body (Figure 2). Below we review current research and present a

preliminary pro forma analysis of the therapeutic and market potential of such a combined innate- adaptive immunotherapy approach, which has the potential to enhance therapy efficacy and efficien- cy, while reducing overall development costs.

Cancer on the ropes: current research supports innate-adaptive immunotherapies Research shows that many, if not most, cancer cells employ CD47 to conceal themselves from macrophages. The two classes of innate checkpoint inhibitors in clinical trials are IgG4 monoclonal antibodies targeting CD47, and SIRP-Fc fusion proteins, which also bind to CD47 on body cells. Since 2014, six developers have initiated 14 clinical studies, including eight Phase I and two Phase II studies testing CD47 antibodies, and four Phase I trials testing SIRP fusion proteins.

IgG4 CD47 antibodies Preclinical and early clinical studies have demon- strated the efficacy of CD47 antibodies against a range of cancers as a monotherapy and combined with adaptive immune therapies. The first and most advanced is Hu5F9-G4 (5F9),

which was engineered with a human IgG4 Fc domain isotype. In addition to blocking the CD47 ‘don’t eat me’ signal, the IgG4 Fc domain provides an additional ‘eat me’ signal via interacting with the Fc receptor on macrophages and facilitates phagocytosis of cancer and other abnormal cells. Yet, the IgG4 Fc domain has minimal affinity for NK cells and does not mediate complement depen- dent cytotoxicity. This is critical because antibodies with other Fc domain isotypes, such as IgG1, can stimulate innate immune attacks against normal tissues that also express CD47. In preclinical testing, 5F9 was broadly active

against a wide range of hematologic malignancies including acute myeloid leukaemia (AML), non- Hodgkin’s lymphoma (NHL), cutaneous T-cell lym- phoma, acute lymphoblastic anaemia, and multiple myeloma1, as well as solid tumours including breast, ovarian, colon, liver and brain cancers2-4. 5F9 clinical trials beginning in 2014 showed the

treatment was well-tolerated, with manageable and mostly minor side-effects and initial efficacy against AML and solid tumours, without reaching a maximum tolerated dose up to 45mg/kg5-7. Clinical trials of another anti-CD47 monoclonal antibody, CC-90002, began in 2015 after preclinical

Drug Discovery World Spring 2019

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