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Small-molecular-weight antibody-mimicking structures for therapeutic applications

English title Small-molecular-weight antibody-mimicking structures for therapeutic applications
Applicant Heinis Christian
Number 123524
Funding scheme SNSF Professorships
Research institution
Institution of higher education EPF Lausanne - EPFL
Main discipline Molecular Biology
Start/End 01.09.2009 - 31.08.2013
Approved amount 1'586'876.00
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Keywords (9)

Antibody; Peptide; Therapy; Small molecule; Phage display; Combinatorial chemistry; Drug development; Peptidomimetic; Protease inhibitor

Lay Summary (English)

Lead
Lay summary
We have recently developed small antibody-mimicking structures that bind with high affinities and specificities to disease relevant targets. The aim of this study is to further develop these molecules and to test their therapeutic potential in vivo. The excellent binding properties of antibodies and the emergence of techniques to create antibodies with tailored specificities have led to their use as therapeutic agents. In recent years several monoclonal antibodies have entered the clinic and have proved to be very powerful drugs for the treatment of serious medical conditions. However, due to their large molecular mass (150'000 Da) monoclonal antibodies have limitations such as the need for parenteral application by injection, poor tissue penetration, and expensive manufacturing costs.Together with Sir Gregory Winter at the Laboratory of Molecular Biology (LMB) in Cambridge, UK, I had recently created antibody-mimicking structures with a small molecular mass (< 2000 Da). The molecules are built of linear polypeptides that are bent around small molecule scaffolds. By varying the sequences of the peptides we were able to generate molecules with tailored binding specificities in a combinatorial approach based on phage display technology. We could isolate binders with high affinities to the human disease targets plasma kallikrein, urokinase-type plasminogen activator (uPA) and cathepsin G.The goal of this project is to further develop the small antibody-mimicking structures and to assess their therapeutic potential in vivo. Towards this end, we will create new antibody mimic designs with different small molecular scaffolds, peptide loop lengths and numbers. Furthermore, we will test new chemical reactions to anchor the linear peptides to the small molecule cores. And most importantly, we will test the stability, the pharmacokinetics and the therapeutic effect of the antibody mimics in vivo. As first priority we will focus on inhibitors of plasma kallikrein and urokinase-type plasminogen activator (uPA) for the treatment of hereditary angioedema and cancer. The project may yield lead compounds for the further development into a therapy for patients. Positive results would also encourage our team and possibly other research groups to develop small-molecule-weight antibody-mimicking structures that bind to other disease targets. The antibody-mimicking structures as well as the technology to develop these molecules may be translated into a business. Furthermore it may accentuate the strong position of Switzerland in biomedical research.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries
Chen Shiyu, Rebollo Inmaculada Rentero, Buth Sergey A., Morales-Sanfrutos Julia, Touati Jeremy, Leiman Petr G., Heinis Christian (2013), Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 135(17), 6562-6569.
Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy
Baeriswyl Vanessa, Calzavarini Sara, Gerschheimer Christiane, Diderich Philippe, Angelillo-Scherrer Anne, Heinis Christian (2013), Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy, in JOURNAL OF MEDICINAL CHEMISTRY, 56(9), 3742-3746.
Improving Binding Affinity and Stability of Peptide Ligands by Substituting Glycines with D-Amino Acids
Chen Shiyu, Gfeller David, Buth Sergey A., Michielin Olivier, Leiman Petr G., Heinis Christian (2013), Improving Binding Affinity and Stability of Peptide Ligands by Substituting Glycines with D-Amino Acids, in CHEMBIOCHEM, 14(11), 1316-1322.
Phage display libraries of differently sized bicyclic peptides
Rebollo Inmaculada Rentero, Angelini Alessandro, Heinis Christian (2013), Phage display libraries of differently sized bicyclic peptides, in MEDCHEMCOMM, 4(1), 145-150.
Phage selection of bicyclic peptides
Rebollo Inmaculada Rentero, Heinis Christian (2013), Phage selection of bicyclic peptides, in METHODS, 60(1), 46-54.
Polycyclic Peptide Therapeutics
Baeriswyl Vanessa, Heinis Christian (2013), Polycyclic Peptide Therapeutics, in CHEMMEDCHEM, 8(3), 377-384.
Bicyclic peptide inhibitor reveals large contact interface with a protease target.
Angelini Alessandro, Cendron Laura, Chen Shiyu, Touati Jeremy, Winter Greg, Zanotti Giuseppe, Heinis Christian (2012), Bicyclic peptide inhibitor reveals large contact interface with a protease target., in ACS chemical biology, 7(5), 817-21.
Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologues while sparing paralogous proteases.
Baeriswyl Vanessa, Rapley Helen, Pollaro Lisa, Stace Catherine, Teufel Dan, Walker Edward, Chen Shiyu, Winter Greg, Tite John, Heinis Christian (2012), Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologues while sparing paralogous proteases., in ChemMedChem, 7(7), 1173-6.
Bicyclization and Tethering to Albumin Yields Long-Acting Peptide Antagonists
Angelini Alessandro, Morales-Sanfrutos Julia, Diderich Philippe, Chen Shiyu, Heinis Christian (2012), Bicyclization and Tethering to Albumin Yields Long-Acting Peptide Antagonists, in JOURNAL OF MEDICINAL CHEMISTRY, 55(22), 10187-10197.
Chemical macrocyclization of peptides fused to antibody fc fragments.
Angelini Alessandro, Diderich Philippe, Morales-Sanfrutos Julia, Thurnheer Sarah, Hacker David, Menin Laure, Heinis Christian (2012), Chemical macrocyclization of peptides fused to antibody fc fragments., in Bioconjugate chemistry, 23(9), 1856-63.
Measuring net protease activities in biological samples using selective peptidic inhibitors.
Pollaro Lisa, Diderich Philippe, Angelini Alessandro, Bellotto Silvia, Wegner Hermann, Heinis Christian (2012), Measuring net protease activities in biological samples using selective peptidic inhibitors., in Analytical biochemistry, 427(1), 18-20.
Structurally diverse cyclisation linkers impose different backbone conformations in bicyclic peptides.
Chen Shiyu, Morales-Sanfrutos Julia, Angelini Alessandro, Cutting Brian, Heinis Christian (2012), Structurally diverse cyclisation linkers impose different backbone conformations in bicyclic peptides., in Chembiochem : a European journal of chemical biology, 13(7), 1032-8.
Bicyclic peptide antagonists derived from genetically encoded combinatorial libraries.
Heinis Christian (2011), Bicyclic peptide antagonists derived from genetically encoded combinatorial libraries., in Chimia, 65(9), 677-9.
Enzymatic cyclisation of peptides with a transglutaminase.
Touati Jeremy, Angelini Alessandro, Hinner Marlon J, Heinis Christian (2011), Enzymatic cyclisation of peptides with a transglutaminase., in Chembiochem : a European journal of chemical biology, 12(1), 38-42.
Post-translational modification of genetically encoded polypeptide libraries.
Angelini Alessandro, Heinis Christian (2011), Post-translational modification of genetically encoded polypeptide libraries., in Current opinion in chemical biology, 15(3), 355-61.
Screening of large molecule diversities by phage display.
Rentero Inmaculada, Heinis Christian (2011), Screening of large molecule diversities by phage display., in Chimia, 65(11), 843-5.
Strategies to prolong the plasma residence time of peptide drugs
Pollaro L, Heinis C (2010), Strategies to prolong the plasma residence time of peptide drugs, in MedChemComm, 1(5), 319-324.
Phage selection of cyclic pepide antagonists with increased stability toward intestinal proteases
Baeriswyl Vanessa, Phage selection of cyclic pepide antagonists with increased stability toward intestinal proteases, in PEDS.

Collaboration

Group / person Country
Types of collaboration
Bicycle Therapeutics Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Padua Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCS Fall Meeting, EPFL Lausanne Talk given at a conference 06.09.2013 Lausanne, Switzerland Heinis Christian;
ISACS11, Challenges in Chemical Biology, Boston Talk given at a conference 24.07.2013 Boston, United States of America Heinis Christian;
Universität Tübingen Talk given at a conference 19.07.2013 Tübingen, Germany Heinis Christian;
23rd American Peptide Symposium, Hawaii Talk given at a conference 23.06.2013 Kona, United States of America Heinis Christian;
ESBOC, Chemical probes for cellular processes Talk given at a conference 17.06.2013 Gregynog, Great Britain and Northern Ireland Heinis Christian;
ECCLS, Chemistry for life sciences, Barcelona Talk given at a conference 10.06.2013 Barcelona, Spain Heinis Christian;
TU Dortmund / Max Planck Institute für Mol. Physiologie, Dortmund Talk given at a conference 04.06.2013 Dortmund, Germany Heinis Christian;
University of Berne, Mini-Symposium Chemical Biology Talk given at a conference 26.04.2013 Berne, Switzerland Heinis Christian;
KTH Royal Institute of Technology Talk given at a conference 08.03.2013 Stockholm, Sweden Heinis Christian;
11th Status Seminar Chemical Biology Talk given at a conference 14.02.2013 Frankfurt, Germany Heinis Christian;
PEGS Europe Talk given at a conference 04.11.2012 Vienna, Austria Heinis Christian;
Protein Engineering for Biocatalysis Talk given at a conference 31.08.2012 Greifswald, Germany , Germany Heinis Christian;
RICT, International Conference in Medicinal Chemistry Talk given at a conference 04.07.2012 Poitiers, France, France Heinis Christian;
Workshop Molecular Determinants of Bacterial Diseases Talk given at a conference 04.06.2012 Naples, Italy, Italy Heinis Christian;
PEGS Summit Talk given at a conference 30.04.2012 Boston, USA, United States of America Heinis Christian;
Gordon Research Conference Talk given at a conference 12.02.2012 Ventura, USA , United States of America Heinis Christian;
University of Zurich, Institute of Molecular Cancer Research Talk given at a conference 16.01.2012 Zurich, Switzerland , Switzerland Heinis Christian;
Natural Product to Drug (NP2D) Conference Talk given at a conference 05.12.2011 Zermatt, Switzerland, Switzerland Heinis Christian;
Peptide Drug Discovering & Manufacturing Conference Talk given at a conference 15.11.2011 Berlin, Germany, Germany Heinis Christian;
R&D Novel Protein Therapeutics Talk given at a conference 27.09.2011 Berlin, Germany, Germany Heinis Christian;
ASMC Talk given at a conference 23.08.2011 Saint Petersburg, Russia, Russia Heinis Christian;
International Symposium on Medicinal Chemistry Talk given at a conference 23.08.2011 St. Petersburgh, Russia, Russia Heinis Christian;
BBBC Edinburgh Talk given at a conference 20.07.2011 Edinburgh, UK, Great Britain and Northern Ireland Heinis Christian;
Biologics&Biotherapeutics Congress Talk given at a conference 20.07.2011 Edinburgh, UK, Great Britain and Northern Ireland Heinis Christian;
Institute of Biotechnology, Vilnius University Talk given at a conference 21.06.2011 Vilnius, Lithuania, Lithuania Heinis Christian;
Joined Symposiums ETH, EPFL, Tokyo Tech, Lausanne Talk given at a conference 10.06.2011 Tokyo, Japan Heinis Christian;
Japanes-Swiss Symposium Chemical Biology Talk given at a conference 09.06.2011 EPFL, Lausanne, Switzerland Heinis Christian;
Drug Discovery Leaders Talk given at a conference 08.06.2011 Zurich, Switzerland, Switzerland Heinis Christian;
Leaders in Drug Discovery Talk given at a conference 08.06.2011 Zurich, Switzerland, Switzerland Heinis Christian;
TIDES Talk given at a conference 25.05.2011 Boston, USA, United States of America Heinis Christian;
TIDES Talk given at a conference 25.05.2011 Boston, USA, United States of America Heinis Christian;
PepTalk Talk given at a conference 13.01.2011 San Diego, USA, United States of America Heinis Christian;
PepTalk Talk given at a conference 12.01.2011 San Diego, USA, United States of America Heinis Christian;
Next Generation Protein Therapeutics Conference Talk given at a conference 28.09.2010 Brussels, Belgium, Belgium Heinis Christian;
Miptec Talk given at a conference 24.09.2010 Basel, Switzerland, Switzerland Heinis Christian;
31st European Peptide Symposium Talk given at a conference 06.09.2010 Copehagen, Denmark, Denmark Heinis Christian;
PEGS Europe Talk given at a conference 06.09.2010 Hannover, Germany, Germany Heinis Christian;
2nd International Symposium on DNA-Encoded Chemical Libraries Talk given at a conference 20.08.2010 Zurich, Switzerland, Switzerland Heinis Christian;
Young Faculty Meeting Talk given at a conference 25.06.2010 Bern, Switzerland, Switzerland Heinis Christian;
IBC conference Talk given at a conference 21.06.2010 San Francisco, USA, United States of America Heinis Christian;
Advances in Antibody and Peptide Therapeutics Talk given at a conference 08.06.2010 Berlin, Germany, Germany Heinis Christian;
PEGS Summit Talk given at a conference 18.05.2010 Boston, USA, United States of America Heinis Christian;
Advancing Protein Therapeutics Conference Talk given at a conference 21.04.2010 Frankfurt, Germany, Germany Heinis Christian;
Proteins Congress Talk given at a conference 30.10.2009 Berlin, Germany, Germany Heinis Christian;
BioMed Conference Talk given at a conference 27.10.2009 Barcelona, Spain, Spain Heinis Christian;
Nachwuchswissenschaftler Symposium Talk given at a conference 29.09.2009 Hannover, Germany, Germany Heinis Christian;
Peptides Europe Conference Talk given at a conference 18.09.2009 Berlin, Germany , Germany Heinis Christian;


Self-organised

Title Date Place
Young Faculty Meeting 16.06.2011 Berne, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Pharmaceutical Sciences, Career Day 08.06.2010 University of Geneva, Geneva, Switzerland, Switzerland Heinis Christian;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Young Researcher MedChemWatch International 2011

Awards

Title Year
EFMC Prize for Young Medicinal Chemist in Academia 2011

Use-inspired outputs


Start-ups

Name Year
Bicycle Therapeutics 2009

Associated projects

Number Title Start Funding scheme
146794 Bicyclic peptide-cytotoxic drug conjugates for cancer therapy 01.09.2013 Project funding (Div. I-III)

Abstract

The excellent binding properties of antibodies and the emergence of techniques to create antibodies with any specificity have led to their use as therapeutic agents. In recent years several monoclonal antibodies have entered the clinic and have proved to be very powerful drugs for the treatment of serious medical conditions. However, due to their large molecular mass (150’000 Da) monoclonal antibodies have limitations such as the need for parenteral application by injection, poor tissue penetration, and expensive manufacturing costs.In my postdoctoral studies in the group of Sir Gregory Winter at the Laboratory of Molecular Biology (LMB) in Cambridge, UK, I proposed a strategy to generate small-molecular-weight antibody-mimicking structures by deforming peptide chains and anchoring them around small molecule building blocks. I created large combinatorial repertoires of such antibody mimics (> 4 billion different molecules) by reacting phage-displayed peptides with small molecule scaffolds. In iterative affinity selections I could isolate binders with high affinities to the human disease targets plasma kallikrein, urokinase-type plasminogen activator (uPA) and cathepsin G. The plasma kallikrein binders efficiently blocked contact activation in human plasma and may be used in cardiopulmonary bypass surgery to suppress the activation of plasma proteases upon contact of the blood with artificial surfaces (please see the manuscript Heinis, C. et al., enclosed in the application). In future, I plan to i) test the therapeutic potential of the generated binders in animal models, ii) generate antibody-mimicking structures to other protein targets iii) develop chemical scaffolds for the creation of new antibody-mimic designs, iv) test new chemical reactions to modify phage-displayed peptides, and v) spin-off the technology in a start-up company.
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