Technology

An innovative approach to targeting disease

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Our technology targets aberrant, overactive macrophages, the source of many diseases

Macrophage Therapeutics is using its Manocept technology to engineer novel compounds that target activated macrophages by binding to the mannose receptor or CD206 on the macrophage cell surface with high binding affinity of 3X10-11 affinity. These synthetic compounds have antibody-like properties but with advantages that can improve dosing options.

The Manocept platform is a clinically-proven technology currently being used in an FDA-approved product that has potential broad therapeutic application across several disease areas including cancer, autoimmune, CNS, cardiovascular, inflammatory and infectious diseases. Preclinical studies are ongoing in many of these diseases. The Manocept technology is proprietary and patent protected, and Navidea has licensed all of their intellectual property to Macrophage Therapeutics for all therapeutic applications.

The four prongs of our approach

A metaphor for understanding the potential of our Manocept technology

References for Manocept's Potential Therapeutic Applications

General

Gordon S. Alternative activation of macrophages. Nature Rev. Immunol 2003;3:23–35.
Mills, C., & Ley, K. (2014). M1 and M2 Macrophages: The Chicken and the Egg of Immunity. J Innate Immun Journal of Innate Immunity, 716-726.

Mosser, D., & Edwards, J. (2008). Exploring the full spectrum of macrophage activation. Nat Rev Immunol Nature Reviews Immunology, 460-460.

Geissmann, F., Manz, M., Jung, S., Sieweke, M., Merad, M., & Ley, K. (2010). Development of Monocytes, Macrophages, and Dendritic Cells. Science, 656-661.

Mills, C., Kincaid, K., Alt, J., Heilman, M., & Hill, A. (2000). M-1/M-2 Macrophages and the Th1/Th2 Paradigm. The Journal of Immunology, 6166-6173.

Mills, C. (2012). M1 and M2 Macrophages: Oracles of Health and Disease. Crit Rev Immunol Critical Reviews in Immunology, 463-488.

Cancer Immunotherapy

General

Chen, Peiwen, Matilde Cescon, and Paolo Bonaldo. “Autophagy-mediated Regulation of Macrophages and Its Applications for Cancer.” Autophagy 10.2 (2013): 192-200.

Rozali, Esdy N., Stanleyson V. Hato, Bruce W. Robinson, Richard A. Lake, and W. Joost Lesterhuis. “Programmed Death Ligand 2 in Cancer-Induced Immune Suppression.” Clinical and Developmental Immunology 2012 (2012): 1-8.

Tumor Associate Macrophages

Fridlender, Z. G., A. Jassar, I. Mishalian, L-Cs Wang, V. Kapoor, G. Cheng, J. Sun, S. Singhal, L. Levy, and S. M. Albelda. “Using Macrophage Activation to Augment Immunotherapy of Established Tumours.” Br J Cancer British Journal of Cancer 108.6 (2013): 1288-297.Heusinkveld, Moniek, and Sjoerd H Van Der Burg. “Identification and Manipulation of Tumor Associated Macrophages in Human Cancers.” Journal of Translational Medicine J Transl Med 9.1 (2011): 216.Barin, Jobert G., G. Christian Baldeviano, Monica V. Talor, Lei Wu, Sufey Ong, Farhan Quader, Ping Chen, Dongfeng Zheng, Patrizio Caturegli, Noel R. Rose, and Daniela C̆iháková. “Macrophages Participate in IL-17-mediated Inflammation.” European Journal of Immunology Eur. J. Immunol. 42.3 (2012): 726-36.Noy, Roy, and Jeffrey W. Pollard. “Tumor-Associated Macrophages: From Mechanisms to Therapy.” Immunity 41.5 (2014): 866.Chittezhath, Manesh, Manprit Kaur Dhillon, Jyue Yuan Lim, Damya Laoui, Irina N. Shalova, Yi Ling Teo, Jinmiao Chen, Revathy Kamaraj, Lata Raman, Josephine Lum, Thomas Paulraj Thamboo, Edmund Chiong, Francesca Zolezzi, Henry Yang, Jo A. Van Ginderachter, Michael Poidinger, Alvin S.c. Wong, and Subhra K. Biswas. “Molecular Profiling Reveals a Tumor-Promoting Phenotype of Monocytes and Macrophages in Human Cancer Progression.” Immunity 41.5 (2014): 815-29.
Quail, Daniela F., and Johanna A. Joyce. “Microenvironmental Regulation of Tumor Progression and Metastasis.” Nature Medicine Nat Med 19.11 (2013): 1423-437.Guo, Chunqing, Annicole Buranych, Devanand Sarkar, Paul B. Fisher, and Xiang-Yang Wang. “The Role of Tumor-associated Macrophages in Tumor Vascularization.” Vasc Cell Vascular Cell 5.1 (2013): 20.Movahedi, K., Schoonooghe, S., Laoui, D., Houbracken, I., Waelput, W., Breckpot, K., . . . Ginderachter, J. (2012). Nanobody-Based Targeting of the Macrophage Mannose Receptor for Effective In Vivo Imaging of Tumor-Associated Macrophages. Cancer Research, 4165-4177.

Kaposi Sarcoma

Tudor, S., D. E. Giza, H. Y. Lin, L. Fabris, K. Yoshiaki, L. D’abundo, K. M. Toale, M. Shimizu, M. Ferracin, K. B. Challagundla, M. Angelica Cortez, E. Fuentes-Mattei, D. Tulbure, C. Gonzalez, J. Henderson, M. Row, T. W. Rice, C. Ivan, M. Negrini, M. Fabbri, J. S. Morris, S-C J. Yeung, C. Vasilescu, and G. A. Calin. “Cellular and Kaposi’s Sarcoma-associated Herpes Virus MicroRNAs in Sepsis and Surgical Trauma.” Cell Death Dis Cell Death and Disease 5.12 (2014)Coscoy, Laurent. “Immune Evasion by Kaposi’s Sarcoma-associated Herpesvirus.” Nat Rev Immunol Nature Reviews Immunology 7.5 (2007): 391-401.

Glioblastoma

Ye, X., Xu, S., Xin, Y., Yu, S., Ping, Y., Chen, L., . . . Bian, X. (2012). Tumor-Associated Microglia/Macrophages Enhance the Invasion of Glioma Stem-like Cells via TGF- 1 Signaling Pathway. The Journal of Immunology, 444-453.Zhou, W., & Bao, S. (2014). Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages. Cancers, 723-740.Kennedy, B., Showers, C., Anderson, D., Anderson, L., Canoll, P., Bruce, J., & Anderson, R. (2013). Tumor-Associated Macrophages in Glioma: Friend or Foe? Journal of Oncology, 1-11.Zhou, W., & Bao, S. (2014). Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages. Cancers, 723-740.

Hodgkin Disease

Choe, J., Yun, J., Jeon, Y., Kim, S., Park, G., Huh, J., . . . Kim, J. (2014). Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: A retrospective cohort study. BMC Cancer, 335-335.

Cardiovascular Disease

General

Rickard, A. J., and M. J. Young. “Corticosteroid Receptors, Macrophages and Cardiovascular Disease.” Journal of Molecular Endocrinology 42.6 (2009): 449-59.Croons, Valerie, Wim Martinet, and Guido R.y. De Meyer. “Selective Removal of Macrophages in Atherosclerotic Plaques as a Pharmacological Approach for Plaque Stabilization: Benefits Vs. Potential Complications.” Current Vascular Pharmacology CVP 8.4 (2010): 495-508.

Atherosclerosis

Shalhoub, Joseph, Mika A. Falck-Hansen, Alun H. Davies, and Claudia Monaco. “Innate Immunity and Monocyte-macrophage Activation in Atherosclerosis.” Journal of Inflammation J Inflamm 8.1 (2011)Tabas, Ira. “Macrophage Death and Defective Inflammation Resolution in Atherosclerosis.” Nat Rev Immunol Nature Reviews Immunology 10.2 (2010): 117.Hirata, Yoichiro, Minoru Tabata, Hirotsugu Kurobe, Tatsuo Motoki, Masashi Akaike, Chika Nishio, Mayuko Higashida, Hiroaki Mikasa, Yutaka Nakaya, Shuichiro Takanashi, Takashi Igarashi, Tetsuya Kitagawa, and Masataka Sata. “Coronary Atherosclerosis Is Associated With Macrophage Polarization in Epicardial Adipose Tissue.” Journal of the American College of Cardiology 58.3 (2011): 248-55.Hadri, K. E., D. F. D. Mahmood, D. Couchie, I. Jguirim-Souissi, F. Genze, V. Diderot, T. Syrovets, O. Lunov, T. Simmet, and M. Rouis. “Thioredoxin-1 Promotes Anti-Inflammatory Macrophages of the M2 Phenotype and Antagonizes Atherosclerosis.” Arteriosclerosis, Thrombosis, and Vascular Biology 32.6 (2012): 1445-452.Bukrinsky, Michael, and Dmitri Sviridov. “HIV and Cardiovascular Disease: Contribution of HIV-Infected Macrophages to Development of Atherosclerosis.” Plos Med PLoS Medicine 4.1 (2007)

Infectious Disease

Kaposi Sarcoma

Coscoy, Laurent. “Immune Evasion by Kaposi’s Sarcoma-associated Herpesvirus.” Nat Rev Immunol Nature Reviews Immunology 7.5 (2007): 391-401.

HIV/AIDS

Abbas, Wasim, Muhammad Tariq, Mazhar Iqbal, Amit Kumar, and Georges Herbein. “Eradication of HIV-1 from the Macrophage Reservoir: An Uncertain Goal?” Viruses 7.4 (2015): 1578-598.Herbein, Georges, Gabriel Gras, Kashif Khan, and Wasim Abbas. “Macrophage Signaling in HIV-1 Infection.” Retrovirology 7.1 (2010): 34.Venkataraman, Nitya, Amy L. Cole, Piotr Ruchala, Alan J. Waring, Robert I. Lehrer, Olga Stuchlik, Jan Pohl, and Alexander M. Cole. “Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1.” PLoS Biology Plos Biol 7.4 (2009)

Influenza

Lee, S. M. Y., I. Dutry, and J. S. M. Peiris. “Editorial: Macrophage Heterogeneity and Responses to Influenza Virus Infection.” Journal of Leukocyte Biology 92.1 (2012): 1-4.Perrone, Lucy A., Julie K. Plowden, Adolfo García-Sastre, Jacqueline M. Katz, and Terrence M. Tumpey. “H5N1 and 1918 Pandemic Influenza Virus Infection Results in Early and Excessive Infiltration of Macrophages and Neutrophils in the Lungs of Mice.” PLoS Pathogens 4.8 (2008)

Other

Huang, X., F. Venet, Y. L. Wang, A. Lepape, Z. Yuan, Y. Chen, R. Swan, H. Kherouf, G. Monneret, C.-S. Chung, and A. Ayala. “PD-1 Expression by Macrophages Plays a Pathologic Role in Altering Microbial Clearance and the Innate Inflammatory Response to Sepsis.” Proceedings of the National Academy of Sciences 106.15 (2009)Chentoufi, A., & Benmohamed, L. (n.d.). Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections. Clinical and Developmental Immunology, 1-22.Green, A., Beatty, P., Hadjilaou, A., & Harris, E. (n.d.). Innate Immunity to Dengue Virus Infection and Subversion of Antiviral Responses. Journal of Molecular Biology, 1148-1160.

Exploitation of the Mannose Receptor (CD206) in Infectious Disease Diagnostics and Therapeutics. A. Azad, M. Rajaram and L. Schlesinger; J. Cytol Mol Biol 2014

CNS

General

Ransohoff, R., & Brown, M. (2012). Innate immunity in the central nervous system. Journal of Clinical Investigation J. Clin. Invest., 1164-1171.

Alzheimer’s

Rezai-Zade, K., Gate, D., Gowing, G., & Town, T. (2011). How to Get from Here to There: Macrophage Recruitment in Alzheimer’s Disease. CAR Current Alzheimer Research, 1-8.Cash, J., Kuhel, D., Basford, J., Jaeschke, A., Chatterjee, T., Weintraub, N., & Hui, D. (2012). Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress. Journal of Biological Chemistry, 27876-27884.Rogers, J., & Lue, L. (n.d.). Microglial chemotaxis, activation, and phagocytosis of amyloid β-peptide as linked phenomena in Alzheimer’s disease. Neurochemistry International, 333-340.Luo, X., Ding, J., & Chen, S. (2010). Microglia in the aging brain: Relevance to neurodegeneration. Molecular Neurodegeneration Mol Neurodegeneration, 12-12.

Multiple Sclerosis

Bogie, J., Stinissen, P., & Hendriks, J. (2014). Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathologica Acta Neuropathol, 191-213.Vogel, D., Vereyken, E., Glim, J., Heijnen, P., Moeton, M., Valk, P., . . . Dijkstra, C. (2013). Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. Journal of Neuroinflammation J Neuroinflammation, 35-35.

Parkinson’s

Bogie, J., Stinissen, P., & Hendriks, J. (2014). Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathologica Acta Neuropathol, 191-213.

Auto-Immune

General

Sindrilaru, A., Peters, T., Wieschalka, S., Baican, C., Baican, A., Peter, H., . . . Scharffetter-Kochanek, K. (2011). An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. Journal of Clinical Investigation J. Clin. Invest., 985-997. doi:10.1172/JCI44490.Sharpe, A., Wherry, E., Ahmed, R., & Freeman, G. (2007). The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology Nat Immunol, 239-245.Steinbach, E., & Plevy, S. (2014). The Role of Macrophages and Dendritic Cells in the Initiation of Inflammation in IBD. Inflammatory Bowel Diseases, 166-175.

NASH

Scheja, L., & Kluwe, J. (2014). Arginine and NASH – Do macrophages deliver the first hit? Journal of Hepatology, 260-261.Bieghs, V., Rensen, P., Hofker, M., & Shiri-Sverdlov, R. (2011). NASH and atherosclerosis are two aspects of a shared disease: Central role for macrophages. Atherosclerosis, 287-293.Farrell, G., Mccullough, A., & Day, C. (2013). What is Non-Alcoholic Fatty Liver Disease (NAFLD), and Why is it Important? Non-Alcoholic Fatty Liver Disease A Practical Guide, 1-16.

Hepatitis

Fletcher, N., Sutaria, R., Jo, J., Barnes, A., Blahova, M., Meredith, L., . . . Mckeating, J. (2014). Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner. Hepatology, 1320-1330.Navarro, L., Wree, A., Povero, D., Berk, M., Eguchi, A., Ghosh, S., . . . Feldstein, A. (2014). Arginase 2 deficiency results in spontaneous steatohepatitis: A novel link between innate immune activation and hepatic de novo lipogenesis. Journal of Hepatology, 412-420.Heydtmann, M. (2008). Macrophages in Hepatitis B and Hepatitis C Virus Infections. Journal of Virology, 2796-2802.Revie, D. (2014). Role of macrophages and monocytes in hepatitis C virus infections. World Journal of Gastroenterology WJG, 2777-2777.Pelletier, S., Bedard, N., Said, E., Ancuta, P., Bruneau, J., & Shoukry, N. (2013). Sustained Hyperresponsiveness of Dendritic Cells Is Associated with Spontaneous Resolution of Acute Hepatitis C. Journal of Virology, 6769-6781.

Diabetes

Espinoza-Jiménez, A., Peón, A., & Terrazas, L. (2012). Alternatively Activated Macrophages in Types 1 and 2 Diabetes. Mediators of Inflammation, 1-10.Purwata, T. (2011). High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. JPR Journal of Pain Research, 169-169.Choi, K., Kashyap, P., Dutta, N., Stoltz, G., Ordog, T., Donohue, T., . . . Farrugia, G. (2010). CD206-Positive M2 Macrophages That Express Heme Oxygenase-1 Protect Against Diabetic Gastroparesis in Mice. Gastroenterology.Stefanovic-Racic, M., Yang, X., Turner, M., Mantell, B., Stolz, D., Sumpter, T., . . . O’doherty, R. (2012). Dendritic Cells Promote Macrophage Infiltration and Comprise a Substantial Proportion of Obesity-Associated Increases in CD11c Cells in Adipose Tissue and Liver. Diabetes, 2330-2339.

Liver Disease

Nakashima, H., Ogawa, Y., Shono, S., Kinoshita, M., Nakashima, M., Sato, A., . . . Seki, S. (2013). Activation of CD11b Kupffer Cells/Macrophages as a Common Cause for Exacerbation of TNF/Fas-Ligand-Dependent Hepatitis in Hypercholesterolemic Mice. PLoS ONE.

Lupus

Shirakawa, F., Yamashita, U., & Suzuki, H. (2010). Monocyte (macrophage)-specific antibodies in patients with systemic lupus erythematosus (SLE). Journal of Clinical Immunology J Clin Immunol, 121-129.

Orphan Drug

ALS

Barbeito, A., Mesci, P., & Boillée, S. (2010). Motor neuron–immune interactions: The vicious circle of ALS. Journal of Neural Transmission J Neural Transm, 981-1000.

Cystic Fibrosis

Assani, K., Tazi, M., Amer, A., & Kopp, B. (2014). IFN-γ Stimulates Autophagy-Mediated Clearance of Burkholderia cenocepacia in Human Cystic Fibrosis Macrophages. PLoS ONE.Jeune, K., Jeune, A., Jouneau, S., Belleguic, C., Roux, P., Jaguin, M., . . . Martin-Chouly, C. (2013). Impaired Functions of Macrophage from Cystic Fibrosis Patients: CD11b, TLR-5 Decrease and sCD14, Inflammatory Cytokines Increase. PLoS ONE.Wright, A., Rao, S., Range, S., Eder, C., Hofer, T., Frankenberger, M., . . . Ziegler-Heitbrock, L. (2009). Pivotal Advance: Expansion of small sputum macrophages in CF: Failure to express MARCO and mannose receptors. Journal of Leukocyte Biology, 479-489.

Gaucher Disease

Xu, Y., Jia, L., Quinn, B., Zamzow, M., Stringer, K., Aronow, B., . . . Grabowski, G. (2011). Global gene expression profile progression in Gaucher disease mouse models. BMC Genomics, 20-20.

Our proprietary technology targets disease at the source