Cambridge Healthtech Institute’s Fourteenth Annual Recombinant Protein Therapeutics conference once again profiles the varying designs of therapeutic fusion proteins in differing stages of development, and investigates the challenges
and benefits associated with these promising therapies. By combining modular building blocks that can reach targets not accessible to antibodies, Fusion Protein Therapeutics possess advantages over antibody-based therapies; their customizable functionality
translates into lower patient dosing, reduced production costs, and improved product homogeneity. This conference will disclose how these molecules are being engineered to form more efficacious therapeutics that offer specificity with enhanced stability
and longer half-life. Case studies from international experts will be presented covering R&D through clinical data.
Final Agenda
SUNDAY, JANUARY 7
4:00 - 6:00 pm Pre-Conference Registration
MONDAY, JANUARY 8
7:00 am Registration and Morning Coffee
9:00 Welcome by Conference Organizer
Mary Ruberry, Senior Conference Director, Cambridge Healthtech Institute
9:05 Chairperson’s Opening Remarks
Stefan Schmidt, Ph.D., MBA, CSO, Development and Innovation, Rentschler Biotechnology
9:10 Fusion Proteins: An Intro to the Field and Selected Case Studies from Roche’s Research & Early Development Pipeline
Stefan Weigand, Ph.D., Head, Large Molecule Research, Roche Innovation Center, Roche
Pharma Research & Early Development (pRED)
This talk will introduce the concept of fusion proteins, provide an overview on which fusion proteins are on the market, how they compare to classical antibodies in the same field, and look at general trends for fusion proteins from development pipelines
of biotech and big pharma. In the second part, I will provide examples from Roche’s pipeline how to discover, design, develop, and deliver differentiated, multi-functional therapeutics that allow for tailored solutions for the biological
problem at hand.
9:50 Making Proteins “Druggable”: Fc Fusion Proteins as a Therapeutic Class
Steven Chamow, Ph.D., Principal Consultant, Chamow & Associates, Inc.
Immunoglobulin G has substantial in vivo stability due to its binding to the neonatal Fc receptor (FcRn) which is responsible for IgG recycling. By creating an Fc fusion, a protein with a short in vivo half-life can be transformed into a stable therapeutic product. This technology has been applied broadly and there are now 6 FDA approved products from this therapeutic class. Their structures and properties will be reviewed.
10:20 Networking Coffee Break
10:45 Generating Ion Channel Blocking Antibodies by Fusing Cysteine-Knot Miniproteins into Peripheral CDR Loops
John McCafferty, Ph.D., CEO, Antibody Engineering, IONTAS, Ltd.
Cysteine-knot miniproteins (knottins) have potential as therapeutic agents to block proteases and ion channels involved in cancer, autoimmunity and pain, but suffer from manufacturing difficulties, short half-lives, and a lack of specificity. Using
X-ray crystallography and biochemical assays, we have demonstrated that functional knottins can be inserted into peripheral antibody CDRs via short linkers. Thus, the resulting “KnotbodyTM” retains the advantage of blocking activity
from the knottin while enjoying the extended half-life and additional specificity conferred by the antibody molecule.
11:15 High-Resolution Mass Spectrometry Confirms the Presence of a Hydroxyproline (Hyp) Post-Translational Modification in the GGGGP Linker of an Fc-Fusion Protein
Chris Spahr, Senior Scientist, Therapeutic Discovery, Discovery Attribute Sciences, Amgen,
Inc.
(G4P)n protein linkers were proposed to replace the commonly used (G4S)n linkers recently found to carry heterogeneous xylose-containing O-glycosylation. Using high-resolution mass spectrometry (HR-MS) and MSn, we demonstrated the presence of an unexpected
hydroxylation of a prolyl residue (Hyp) in a (G4P) linker. Further efforts in determining whether the modification is 3-hydroxyproline (3-Hyp) or 4-hydroxyproline (4-Hyp) will be discussed.
11:45 Improving Enzyme-Based Therapy of Acute Lymphoblastic Leukemia: Molecular Design of Human L-Asparaginases
Manfred Konrad, Ph.D., Research Director, Enzyme Biochemistry, Max Planck Institute
for Biophysical Chemistry
Acute lymphoblastic leukemia (ALL), the most common cancer in children, is a genetically heterogenous disease. We designed and engineered human enzyme homologues displaying the clinically established enzyme drug L-asparaginase (L-ASNase) activity with the aim of identifying catalytically efficient variants to substitute for the bacterial enzymes. Furthermore, to increase the serum half-life of the enzymes, we generated biocompatible microcapsules as carriers, thus enhancing serum stability and preventing exposure of the protein to the immune system.
12:15 pm Veltis® Engineered Albumins and Their Potential for Improved Therapeutic Performance
Helen Rawsthorne, Ph.D.,
Senior Research Scientist, Molecular Biology and Fermentation, Albumedix
The natural properties of albumin have ensured its use for decades in enhancing the pharmacokinetic and pharmacodynamic properties of drug candidates. We have designed rationally engineered albumins to enhance these properties. A half-life of more
than double that seen for native sequence albumin is obtainable for therapeutic candidates associated with Veltis® albumins engineered for increased FcRn binding affinity. Newly
developed thio-engineered albumins with additional free thiol groups allow further options for multi-valent site-specific drug loading.
12:45 Enjoy Lunch on Your Own
2:00 Chairperson’s Remarks
John McCafferty, Ph.D., CEO, Antibody Engineering, IONTAS, Ltd.
2:05 Design, Structure and Manufacturability: Lessons Learned from Fusion Proteins
Stefan Schmidt, Ph.D., MBA, CSO, Development and Innovation, Rentschler Biotechnology
Next-generation therapeutic proteins are typically human designed molecules with no counterpart in living organisms. As they have not been selected in a natural evolution process, they can suffer from low expression, mis-assembly and mis-folding,
disulfide scrambling, a tendency to aggregate, and sensitivity to protease degradation. In this presentation, I will show examples from our portfolio and the literature demonstrating how to avoid these product-related impurities by smart fusion
protein design and strategies to eliminate these impurities in efficient bioprocesses.
2:35 Advanced Bi- and Multi-Specific Antibody Derivatives and Fusion Proteins for Targeted Therapy: From Molecular Design to Therapeutic Application
Ulrich Brinkmann, Ph.D., Expert Scientist, Scientific Director, Roche Pharma
Research & Early Development, Roche Innovation Center Munich
‘Success needs Diversity - Diversity breeds Success’: Roche develops bi & multi-functional antibody derivatives in diverse compositions and formats (as opposed to ‘one-size/format-fits-all’ approaches). The presentation will highlight examples of the variety of multi-functional antibody formats, covering examples of diverse molecules in clinical development as well as novel approaches in pre-clinical evaluation.
3:05 Transition to BuzZ Sessions
3:15 BuzZ Sessions with Refreshments
Join your peers and colleagues for interactive roundtable discussions.
4:30 SELECTED POSTER PRESENTATION:
Computational Driven Protein Engineering Platform Enables the Discovery and Development of Next-Gen Antibacterial Therapeutics
Yongliang Fang, Ph.D., Scientist, Thayer School of Engineering, Dartmouth
College
Conventional small-molecule antibiotics only inhibit the growth of MRSA and are known to rapidly induce new resistance once they are applied in the clinic. Therefore, there is a critical need for an alternative approach to combat this threat
to public health. Lysostaphin is an antibacterial enzyme which has drawn the attention of researchers, pharmaceutical companies, and the medical community because of its extraordinary potency against MRSA both in vitro and in vivo.
The success of our methods for deimmunization of lysostaphin demonstrates the potential impact of computationally-driven engineering throughout the biotherapeutic pipeline. In addition, the computational algorithms will also allow us to
develop various types of therapeutic proteins with lower immunogenicities and may ultimately aid the rising tide of biologics that are currently entering the R&D pipeline.
5:00 Protein Engineering to Further Improve Clotting Factor-Fc Fusions and Create Novel FVIIIa Mimetic Bispecific Antibodies
Robert Peters, Ph.D., Senior Vice President, Research, Bioverativ, Inc.
Further protein engineering was performed on clotting factor-Fc fusions with a goal to further improve protection from bleeds provided by a prophylaxis regimen, and to potentially enable subcutaneous administration, while preserving the biology
of the coagulation system. Considerations and the path to creation of rFVIIIFc-VWF-XTEN and rFIX(R338L) Fc-XTEN fusion proteins will be presented, as well as antibody screening methods used to generate a true FVIIIa mimetic bispecific
(FIXa/FX) antibody.
5:30 Designed Ankyrin Repeat Protein as Inhibitors of Clostridium Difficile Toxin B
Zhilei Chen, Ph.D., Associate Professor, Microbial Pathogenesis and Immunology,
Texas A&M College of Medicine
Using phage-panning combined with high-throughput in vitro functional screening, we recently engineered several designed ankyrin repeat protein (DARPin) with picomolar neutralization potency against
C. difficile TcdB, which is 100-1000-fold more potent than bezlotoxumab. These anti-toxin DARPins were found to effectively protect mice against TcdB-associated mortality. Cryo-electromicroscopy studies revealed that binding
of one of these DARPins induced significant conformational change of TcdB, likely rendering it unable to associate with the target receptor.
6:
00 - 7:15 Welcome Reception in the Exhibit Hall with Poster Viewing
7:15 Close of Day
TUESDAY, JANUARY 9
8:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Robert Peters, Ph.D., Senior Vice President, Research, Bioverativ, Inc.
8:35 Combinatorial Protein Engineering of Proteolytically Resistant Mesotrypsin Inhibitors as Candidates for Cancer Therapy
Niv Papo, Ph.D., Group Leader and Assistant Professor, Biotechnology Engineering, Ben-Gurion
University
Our study describes a rapid methodology for identifying mutations that convert the human amyloid precursor protein Kunitz protease inhibitor domain (APPI), a natural substrate of the oncogenic protease mesotrypsin, into a proteolytically
stable high affinity inhibitor of mesotrypsin. We demonstrated that APPIM17G/I18F/F34V acts as a functional inhibitor in cell-based models of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, by solving
the crystal structure of the complex, we uncovered new insights into the structural and mechanistic basis for improved binding and proteolytic resistance.
9:05 Redefinition of ErbB2/3 Tumor Targeting: Novel Platform for Development of Truly Efficient Anti-ErbB Bispecific and Biparatopic Agents
Rastislav Tamaskovic, Ph.D., Senior Scientist,
Biochemistry, University of Zurich
We built a new platform for RTK fingerprinting of tumors under therapy, for identification of points of fragility in oncogene-addicted tumors with the developed acquired resistance, and for the design of prospective therapeutic leads
in a variety of bispecific formats. This novel approach heralds the next generation of ErbB targeting vehicles with beneficial properties owing to maximization of drug potency and minimization of the risk of side and off-target
effects associated with the current drug formats.
9:35 Presentation to be Announced
9:50 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 HERA: Engineering Next Generation TNFR-SF Agonists for Cancer Immunotherapy
Oliver Hill, Ph.D., Vice President, Molecular Biology/Protein Engineering,
Apogenix AG
The HERA technology platform developed by Apogenix is based on trivalent but single-chain molecular mimics of the TNF-SF receptor binding domains (scTNFSF-RBDs) fused to a dimerization scaffold. These hexavalent fusion proteins are
true agonists and their biological activity is, in contrast to agonistic anti-TNFR-SF antibodies, independent of secondary Fc-receptor based crosslinking events. We will present the molecular engineering concept and report on
in vitro and in vivo activities of HERA-CD40L, HERA-CD27L, HERA-GITRL and HERA-CD137L.
11:30 Extended Q&A with Speakers
12:00pm Close of Recombinant Protein Therapeutics Conference