Ali Salanti

Short presentation

Malaria and molecular biology have always been my passion and I focus my interest on exploring the molecular mechanisms behind parasite sequestration in the human placenta with the long-term perspective of aiding malaria sick women with a prophylactic or therapeutic compound. My entire research career is centered around the possibility of translating my research into medical products.  Funded by the Bill and Melinda Gates foundation we identified the antigen, named VAR2CSA, responsible for malaria parasite adhesion and have focused my efforts on making this antigen into a functional vaccine. I have managed to recruit and maintain highly skilled research group and together we have finalized pre-clinical development, GMP manufacturing and two clinical trials in women with VAR2CSA as malaria vaccine. Besides the clinical development, my team and I are involved in a range of project involving malaria pathogenesis and immunology. Recently, in collaboration with Dr. Daugaard, we made the seminal discovery that the CSA found in placenta, mediating parasite adhesion, is also expressed on cancer cells, but no other places in the human body. Our accumulated data demonstrate that VAR2CSA binds all tested cancer cell lines and cancer cell tissues. Drug conjugates based on recombinant VAR2CSA show effective in advanced animal models against a wide range of xenografted tumors and the novel treatment holds the promise to become a novel type of cancer type in cancers where there are currently no treatment. For this research, I have been awarded the very prestigious European Research Council (ERC) Consolidator grant and I am pursuing to develop this towards human clinical testing, and I was recently awarded an ERC PoC grant to pursue translational aspects of my ERC project. Lastly, I have been heading a team effort into developing novel vaccine technologies. This endeavor has resulted in a ground-breaking novel vaccine technology that can deliver virtually any recombinant vaccine antigen on a virus like particle in a dense and highly ordered manner. Both the cancer technology and the VLP technology are spun out of the university as separate companies. Over the last few years I have established 4 companies engaged in clinical development. At UCPH I am heading a lab with 40 people working with me with a high number of post doc employees, and in the past I have successfully taken more than 15 students through a PhD program. I have published 100 publications in these areas of research and submitted 8 patent applications, whereas three patent families has been issued.

CV

Positions and Employment

• 2018 -              Professor in translational microbiology (UCPH)
• 2013 - 2017     Professor (MSO) at University of Copenhagen (ISIM)
• 2008 - 2011     Associate Professor at University of Copenhagen
• 2008 - 2010     Senior research fellow and Group leader “VAR2CSA-team” 
• 2004 - 2007     Post. Doc at CMP at University of Copenhagen
• 2003 - 2007     Consultant for Nordic Vaccine Technology
• 2001 - 2001     Principal Investigator Lica Pharmaceuticals

Other Experience

• CEO of UCPH Spinout company, VAR2Pharmaceuticals.
• CEO of UCPH Spinout company, VARCTDiagnostics
• Member of board in Spinout companies Adaptvac, NextGenVaccines and OncoMal
• Head of research laboratory at Centre for Medical Parasitology
• Ad hoc Peer-reviewer for scientific journals (Nature, PLoS pathogens, JID, Lancet among others)
• Coordinator of several large research consortiums including EU, Gates and Innovation Foundation programs
• Evaluator and referee of International Scientific grant programs including Wellcome Trust and the UK medical Councils.
• Invited speaker at numerous high profiled international meetings, here among: Gordon conferences, ASTMH Meeting and Nobel Seminars

Collaboration with Industry

• Collaboration with Zymeworks (Canada) on developing cancer therapeutics (2015-today)
• Collaboration with Roche Innovation Centre to develop LNA targeted delivery technologies (2017)
• Collaboration with Cilian (Germany) to to express malaria proteins in Tetrahymena. (2010-2014)
• Collaboration with 4sc (Germany) through the PreMalStruct project to develop compounds that can inhibit parasite binding to placental tissue. (2010-2014)
• Collaboration with Expres2ion Biotechnologies (Denmark) and CMC Biologics A/S for producing the VAR2CSA vaccine in a virus free expression system (2012-today)
• Collaboration with Mucosis (Holland) in a EuroStar collaboration to test novel adjuvant systems (2014-2016

My Contributions to Science

1. Malaria Biology:

My research career started with a PhD stipend from the Bill and Melinda Gates foundation where I became a part of a large international endeavor, led by Dr. Patrick Duffy from NIH, with the aim of identifying the molecular background for placental malaria infection. Independently, I identified and characterized the VAR2CSA protein as the principle malaria parasite adhesion ligand mediating parasite adhesion to CSA in the placenta. I described this in two seminal publications published in J.Exp.Med (2003) and Mol.Microbiology (2004). I decided that I would not stop in this area of research until VAR2CSA was moved forward to human testing as a vaccine for pregnant women.

a)     Salanti A, Dahlbäck M, Turner L, Nielsen MA, Barfod L, Magistrado P, Jensen AT, Lavstsen T, Ofori MF, Marsh K, Hviid L, Theander TG. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med. 2004 Nov 1;200(9):1197-203. PMID: 15520249 PMCID: PMC2211857

b)     Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol. 2003 Jul;49(1):179-91. PMID: 12823820

2. Clinical development of a Malaria vaccine

VAR2CSA is a large highly complex multi domain protein and before entering clinical development, we needed to define the exact immunogen. Over a period of 8 years and more than 30 publications, I describe the role of each domain, the immunogenicity in man and mice and the molecular structures. Together with Oxford University we were the first to produce the full length protein and with this in hand we defined the minimal region that could bind CSA with the same affinity as the full length protein. This work was extensively supported through the Bill and Melinda Gates foundation and three EU FP6 programs with me as principle investigator. Having defined the minimal binding region of VAR2CSA we were ready to initiate a clinical development program. Our team was the first ever at University of Copenhagen to be responsible for a GMP manufacturing and sponsor of clinical testing. This endeavor was a close collaboration with CMOs, CROs and clinical sites, and in 2016, led by Associate Professor Morten Nielsen (team VAR2CSA) we finished a phase Ia trial in Germany and in 2017 we finished a phase Ib trial in women in Benin.

a)     Dahlback M, Rask TS, Andersen PH, Nielsen MA, Ndam NT, Resende M, Turner L, Deloron P, Hviid L, Lund O, Pedersen AG, Theander TG, Salanti A: Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in P. falciparum placental sequestration. PLoS Pathog 2006;2:e124. PMID: 17112315 PMCID: PMC1636682

b)     Nielsen MA, Pinto VV, Resende M, Dahlback M, Ditlev SB, Theander TG, Salanti A: Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA. Infect Immun 2009;77:2482-2487. PMID: 19307213 PMCID: PMC2687338

c)     Khunrae P, Dahlback M, Nielsen MA, Andersen G, Ditlev SB, Resende M, Pinto VV, Theander TG, Higgins MK, Salanti A: Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies. J Mol Biol 2010;397:826-834. PMID: 20109466 PMCID: PMC3715698

d)    Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE, Resende M, Agerbaek MO, Andersen D, Berisha B, Ditlev SB, Pinto VV, Nielsen MA, Theander TG, Larsen S, Salanti A: Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J Biol Chem 2012;287:23332-23345. PMID: 22570492 PMCID: PMC3390611

3. Second generation vaccine development.

In 2013 I received a major grant from the Bill and Melinda Gates Foundation (grand challenge program) based on the idea of developing a combinatorial vaccine against placental malaria and HPV induced Cervical Cancer. All recent clinical trials with recombinant malaria (and other) proteins has been a huge disappointment for the field of vaccinology, and there is an increasing awareness that vaccines needs to be delivered as virus like particles (VLP) to induce sufficient high and long lasting IgG titers. This is particular pertinent for a vaccine to pregnant women, as the vaccine needs to be given prior to pregnancy. I developed a strategy to attach VAR2CSA to the surface of the Human Papilloma Virus and together with John Schiller (NIH) we demonstrated that this vaccine was protective against both malaria and HPV. The HPV particle is not very cost effective and is defined by serotypes, thus not giving broad protection. With proof of principle at hand of a dual vaccine, we have now developed a versatile vaccine platform that is manufacturable in E. coli and can delivery several vaccine antigens on the same particle. Using this we are now testing a broadly covering L2 based HPV vaccine combined with both VAR2CSA and Zika antigens – aiming at a cost effective broadly effective vaccine for infectious diseases in adolescent women. The platform has proven to be very effective also at breaking tolerance to self-antigens and we are about to submit a major manuscript on a novel HER2 vaccine to protect and treat HER2 positive cancers, here among breast and bladder cancer. We have submitted a number of patent applications on the technology and have made a spinout company who will drive the commercialization.

a)    Thrane S, Janitzek CM, Matondo S, Resende M, Gustavsson T, de Jongh WA, Clemmensen S, Roeffen W, van d, V, van Gemert GJ, Sauerwein R, Schiller JT, Nielsen MA, Theander TG, Salanti A, Sander AF: Bacterial superglue enables easy development of efficient virus-like particle based vaccines. J Nanobiotechnology 2016;14:30. PMID: 27117585 PMCID: PMC4847360

b)     Susheel K. Singh, Susan Thrane, Christoph M. Janitzek, Morten A. Nielsen, Thor G. Theander, Robert W. Sauerwein, Michael Theisen, Ali Salanti, Adam F. Sander. Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display. Accepted for publication June 2017. Vaccine.

3. Cancer Glycobiology and translation of this research

My extensive work on the understanding of the pathology of placental malaria, led me to understand why VAR2CSA expressing malaria parasites exclusively sequestered in the placenta. This was due to the presence of a distinct carbohydrate modification (CSA), only present in the placenta. We found that this carbohydrate was overexpressed to attract growth factors to mediate rapid growth of the fetus and placenta and to provide the possibility to expand the placental within the uterine tissues. I thought that these are the same features as seen in cancer and a simple experiment by mixing malaria parasites from a pregnant women with cancer cells in vitro demonstrated that indeed VAR2CSA could bind to CSA also on cancer tissues. In a huge multicenter endeavor led by me we demonstrated that the recombinant VAR2CSA binds the vast majority of cancer cells and cancer tissue biopsies with high affinity and high specificity, and very limited binding to normal tissue. I am now dedicated to take this into a phase I trial in cancer patients. Our pre-clinical data demonstrate that upon IV injection, the protein rapidly locates to a xenografted tumor, and if conjugating the protein with a toxin, we can significantly reduce the tumor burden. Besides primary tumors, we have strong data showing that also cancer stem cells, metastases and circulating tumor cells have high levels of this onco-fetal type CSA that can be targeted with VAR2CSA, opening for a multitude of diagnostic and therapeutic possibilities. We have embarged on a clinical development program to test a VAR2CSA drug conjugate in cancer patients, and are in the process of developing processes and analytical tools for GMP production. In collaboration with three hospital in the UK and Canada we have demonstrated that VAR2CSA with high specificity and sensitivity can capture circulating tumor cells from a wide range of tested cancer patients, and we have embarged on a clinical development project to have the methods approved by the FDA for diagnostic and prognostic purposes. We remain to understand the molecular biology behind of-CSA, for example the structure of of-CSA is unknown and the understanding of this combined with understanding of how the modification is initiated could provide ground breaking understanding of Cancer. The Spinout Company VAR2Pharmaceuticals is driving the development of the therapeutic product pipeline and the spinout VARCT Diagnostics holds the rights to use VAR2CSA to capture circulating tumor cells

a)     Salanti A, Clausen TM, Agerbaek MO, Al NN, Dahlback M, Oo HZ, Lee S, Gustavsson T, Rich JR, Hedberg BJ, Mao Y, Barington L, Pereira MA, LoBello J, Endo M, Fazli L, Soden J, Wang CK, Sander AF, Dagil R, Thrane S, Holst PJ, Meng L, Favero F, Weiss GJ, Nielsen MA, Freeth J, Nielsen TO, Zaia J, Tran NL, Trent J, Babcook JS, Theander TG, Sorensen PH, Daugaard M: Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer Cell 2015;28:500-514. PMID: 26461094 PMCID: PMC4790448

b)     Sugiura N, Clausen TM, Shioiri T, Gustavsson T, Watanabe H, Salanti A: Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library. Glycoconj J 2016. PMID: 27287227

c)     Clausen TM, Marina Ayres Pereira, nakouzi N, Oo, Agerbaek MO, Lee S, Orum-Madsen M, Kristensen A, Naggar A, Grandgenett P, Grem L, Hollingsworth M, Holst PJ, Theander G, Sorensen PH, Daugaard M, Salanti A: Oncofetal Chondroitin Sulfate Glycosaminoglycans are Key Players in Integrin Signaling and Tumor Cell Motility; Molecular Cancer Research. 2016;14:1288-1299. PMID: 27655130

d)     Seiler R, Oo HZ, Tortora D, Clausen TM, Wang CK, Kumar G, Pereira MA, Ørum-Madsen MS, Agerbæk MØ, Gustavsson T, Nordmaj MA, Rich JR, Lallous N, Fazli L, Lee SS, Douglas J, Todenhöfer T, Esfandnia S, Battsogt D, Babcook JS, Al-Nakouzi N, Crabb SJ, Moskalev I, Kiss B, Davicioni E, Thalmann GN, Rennie PS, Black PC, Salanti A, Daugaard M. An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-resistant Bladder Cancer. Eur Urol. 2017 Apr 10. PMID: 28408175

A complete List of Published Work is available at www.ncbi.nlm.nih.gov/pubmed/?term=salanti+A

Recent funding awards

• Danish Cancer Society. Therepeutic development of a anti-cancer therapy. 0.5M Euro (2017)
• ERC PoC for using rVAR2 to capture circulating tumor cells 0.2M Euro (2017)
• Danish Research Councils. The role of onco-fetal carbohydrates in cancer. 0.4M Euro (2017)
• ERC consolidator grant to develop rVAR2 to a therapeutic compound. 2M Euro (2014)
• Department of Defense (DoD). Using VAR2CSA to target breast cancer. 250.000 USD
• EU FP7. Clinical development of a placental malaria vaccine. 7.000.000 Euro
• Eurostars. Adjvuant testing. Size/Duration: 130.000 Euro (2012-14)
• Gates Foundation. Combinatorial vaccine against malaria and HPV. 675.000 Euro (2012-14)
• European Vaccine Initiative (EVI). Process development of a placental malaria vaccine. Size/Duration: 1.000.000 Euro 2012-2015
• Danish National Advanced Technology Foundation (HFT). Development and preclinical safety Assessment of a placental malaria vaccine Size/Duration: 2.000.000 Euro 2011-2014
• UCPH  Programme of Excellence. Plasmodium falciparum malaria pathogenesis and immunity Size/Duration: 2.500.000 Euro, 5 years (2012)

Publications: 100 Peer reviewed published papers (96 on pubmed, 3 in press and two not indexed on pubmed) + 9 patent applications (three granted).   

Management experience

I am currently leading a team of 38 research scientists ranging from master students to associate professors. I have been the grant holder and coordinator of several major FP7 EU supported projects as well as major Gates Foundations grants, as well as coordinator of a large HTF (Højteknologifonds) consortium. I the recent years I was awarded an ERC consolidator grant and ERC PoC grant to further consolidate my research tem. Management experience thus entails both consortium coordination, coordination of large international research teams, reporting to funding agencies as well as public outreach disseminating key results.

Innovation

Through our research and development at University of Copenhagen I have made 5 spinout companies, founded a broad and strong patent portefolie within vaccine development, vaccine delivery, cancer therapy and cancer diagnostics. In 2012 VAR2Pharmaceuticals and OncoMal was established and is now based in Copenhagen (COBIS) and Vancouver supported by private investors. In 2016-17 we made the spinout companies NextGen vaccines and AdaptVac based in the bioscience park in Hørshol as a joint venture with Expres2ion Biotechnologies and in 2017 we established VARCT Diagnstostics which is now running a number of clinic feasibility studies in cancer diagnostics around the world. Based on translational research our Centre for Medical Parasitology at UCPH was awareded with a "Centre of Excellence" Price in 2016.