The customizable functionality of Fusion Protein Therapeutics creates advantages over antibody-based therapies by combining modular building blocks that can reach targets not accessible to antibodies. Additional advantages include lower patient dosing, reduced production costs, and improved product homogeneity. The “Fusion Protein Therapeutics” conference explores the varying constructs and ‘designs’ of fusion protein molecules, and will disclose how they are being engineered to form more efficacious therapeutics that offer specificity with enhanced stability and longer half-life. Experts will present case studies from R&D through clinical data, and will share the results they’ve achieved.
Final Agenda
Recommended Short Courses*
SC4:The Multi-Attribute Method (MAM) for Improving Product and Process Development - Detailed Agenda
SC9: Target Selection for Biologics - Detailed Agenda
*Separate registration required
MONDAY, MAY 1
7:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Fredrik Frejd, Ph.D., CSO, Affibody AB
8:40 KEYNOTE PRESENTATION: From Cytokine Traps to Antibody-Based Protein Therapeutics: A Scientific Journey
Aris N. Economides, Ph.D., Executive Director; Genome Engineering Technologies, and Skeletal Diseases TFA, Co-Founder & Head of Functional Modeling; Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc.
Engineered proteins such as receptor ectodomain-Fc fusions and cytokine traps are complex fusion proteins comprised of two different receptor ectodomains fused to human Fc, and in as much as they are potent and highly specific, they also present engineering and production challenges. Technological advances in monoclonal antibody generation and production have largely supplanted cytokine trap technology and have also enabled the engineering of antibody-based therapeutics with novel properties. Examples of these technologies and their applications for the generation of therapeutics will be discussed.
9:10 FEATURED PRESENTATION: Fusion Proteins: Case Studies from Roche’s Research & Early Development Pipeline
Stefan Weigand, Ph.D., Head, Large Molecule Research, Roche Pharma Research and Early Development (pRED), F. Hoffmann-La Roche, Ltd.
This talk will briefly introduce the concept of fusion proteins and 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. Lastly, I will raise challenges and opportunities for future applications of fusion proteins.
9:40 Fusion Protein Approaches to Generate Biobetters – Current Status and Future Outlook
Stefan Schmidt, Ph.D., M.B.A., Vice President, Process Science and Production, Rentschler Biotechnology
Next-generation biologics with enhanced properties are one of the fastest growing protein classes. These biobetters typically demonstrate improved pharmacokinetics or more selective targeting. In many cases, this is achieved by fusing the therapeutic entity to other protein modules influencing plasma half-life or reducing off-target toxicity. Here I highlight the current strategies to generate biobetters with these superior properties while describing their benefits and limits in examples from the present development pipeline.
10:10 Coffee Break
10:50 PASylation: The Biological Alternative to PEGylation for Plasma Half-Life Extension and Beyond
Arne Skerra, Ph.D., Professor, Technische Universität Munich; and Chairman & Founder, XL-protein GmbH
Fusion of proteins or peptides with conformationally disordered polypeptides comprising the L-amino acids Pro, Ala, and/or Ser (PAS) is a beneficial way to enlarge the hydrodynamic volume and retard kidney clearance, a common drawback during biological drug development. PAS sequences are strongly hydrophilic, uncharged biological polymers with biophysical properties surprisingly similar to PEG while, in contrast, allowing traceless metabolization. Case studies on the route to clinical development will be presented.
11:20 Hexavalent Agonists Targeting Co-Stimulatory Receptors of the TNFR-Superfamily
Oliver Hill, Ph.D., Vice President, Molecular Biology, APOGENIX AG
TNFRSF targeting compounds with a solely agonistic activity on immune cells are still rare. Apogenix’s single-chain-based fusion proteins mimic the three-dimensional organization of the natural ligands (the TNFSF-proteins). In contrast to antibodies, their agonistic activity does not rely on secondary crosslinking events in vitro nor in vivo. We will present the modular engineering concept and the current results obtained for the hexavalent CD40-, 4-1BB-, GITR-, HVEM- and CD27-agonists.
11:50 Monomeric Fc Platform for Monomeric Fusion Proteins
Lu Shan, Ph.D., Scientist II, Antibody Discovery & Protein Engineering, MedImmune/AstraZeneca
Monomeric Fc or Fc halfmer is a versatile format for generating monovalent fusion proteins. We present a strategy that generated a stable Fc monomer using rational design combined with in vitro evolution methodologies, resulting in monomeric Fc fusion proteins with FcRn binding and serum half-life comparable to wildtype IgG.
12:20 pm Sponsored Presentation (Opportunity Available)
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:50 Session Break
2:20 Problem-Solving Breakout Discussions
These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.
Fusion Protein Versus Chemical Conjugation Strategies For Plasma Half-Life Extension
Arne Skerra, Ph.D., Professor, Technische Universität Munich; and Chairman & Founder, XL-protein GmbH
- Fusion approaches with Fc domains, albumin, or PEG-mimetic polypeptides (e.g. PAS)
- Implications for the production organism
- Chemical conjugation with PEG, lipids, or polysaccharides
- Choice of chemical coupling procedure
Pharmacokinetics and Stability Challenges in Fusion Protein Therapeutics
Lu Shan, Ph.D., Scientist II, Antibody Discovery & Protein Engineering, MedImmune/AstraZeneca
- What are some of the stability challenges that have been encountered?
- What kinds of half-life extension are achieved?
- Are there certain sequence liabilities or PTMs that contribute more to the stability or half-life issues?
Bioconjugation Strategies for Next-Generation Biologics
James Patterson, Ph.D., Senior Scientist, Project Leader, Antibody Technologies and Chemical Biology, Sorrento Therapeutics, Inc.
- Advantages and drawbacks of conventional conjugation methods
- Site-specific conjugation approaches for defined conjugates
- Solving serum stability problems with chemical and protein engineering
- Therapeutic applications of bioconjugates beyond ADCs
3:20 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 Chairperson’s Remarks
Sir Gregory Winter, Ph.D., FRS, Master, Trinity College and Co-Founder and Director, Bicycle Therapeutics
Bicycles® are a novel therapeutic class of constrained bicyclic peptides that combine antibody-like affinity and selectivity with small molecule-like tissue penetration, tunable exposure and chemical synthesis. They have potential in many indications, including oncology, where Bicycles’ unique properties have been used to develop Bicycle Drug Conjugates™ (BDCs); a novel toxin delivery platform which greatly improves toxin loading into tumour tissues. This presentation will describe both the Bicycle® and BDC platforms.
4:55 Young Scientist Keynote: Programming Proteins by Deep Sequencing and Design
Tim Whitehead, Ph.D., Assistant Professor, Chemical Engineering and Materials Science, Michigan State University
Next-generation sequencing has presented protein scientists with the ability to observe entire populations of molecules before, during, and after a high-throughput screen or selection for function. My group leverages this unprecedented wealth of sequence-function information to design and engineer protein affinity, specificity, and function and to infer structural complexes of proteins. My talk will present an overview of the above and detail methodological improvements that enable the engineering work.
5:40 Welcome Reception in the Exhibit Hall with Poster Viewing
6:55 End of Day
TUESDAY, MAY 2
8:00 am Registration and Morning Coffee
8:25 Chairperson’s Remarks
Stefan Weigand, Ph.D., Head, Large Molecule Research, Roche Pharma Research and Early Development (pRED), F. Hoffmann-La Roche, Ltd.
8:30 Engineering an Affibody Fusion Protein Trap towards Therapeutic Blocking of IL-17 in Humans
Fredrik Frejd, Ph.D., CSO, Affibody AB
Psoriasis is an IL-17 driven disease. An Affibody® based 18.6 kDa ligand trap was engineered to block IL-17 with femtomolar affinity. The trivalent bispecific fusion protein blocks IL-17 with unparalleled affinity and display long plasma half-life as shown in man. Early development and data from Phase I/II will be presented.
9:00 PolyXen: A Polysialylation Technology for Enhancing Therapeutic Proteins and Its Clinical Application
Curtis Lockshin, Ph.D., Chief Scientific Officer, Xenetic Biosciences, Inc.
PolyXen™ is a proprietary platform for conjugating polysialic acid (PSA) to protein or peptide therapeutics, which can improve their pharmacological properties. Preclinical and human clinical data has been generated with a number of compounds, including recombinant Factor VIII, rhEPO, and oxyntomodulin. Therapeutic proteins polysialylated with the PolyXen platform have displayed extended circulating half-life, improved thermodynamic stability and protease resistance, while retaining pharmacological activity. We have seen no evidence to date of PSA- induced immunogenicity, an issue commonly associated with PEG.
9:30 A New Fab-Fusion Protein Therapeutic for Enzymatic Targeting
Michiel E. Ultee, Ph.D., Principal, Ulteemit BioConsulting, LLC
We describe the design, development and manufacture of a unique antibody-fusion protein consisting of a Fab-linked enzyme rather than the more typical Fc-linked fusion protein. VAL-1221, a preclinical product candidate for glycogen-storage diseases, contains a humanized anti-dsDNA Fab genetically linked to the acid alpha glucosidase enzyme (GAA). CHO-cell production was straightforward, but purification was challenging. The final process overcame these challenges for production of clinical material at the 500L scale.
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Development of Luspatercept: A Receptor Fusion Protein Engineered to Treat Anemia caused by Ineffective Erythropoiesis
Rajasekhar Suragani, Ph.D., Associate Director, Acceleron Pharma, Inc.
Soluble receptor-Fc fusion proteins, also known as ligand TRAPs, are often used as high-affinity decoys to block signaling through their cognate receptors. Transforming Growth Factor-Beta (TGF-beta) superfamily member activin receptor type IIB (ActRIIB) binds to multiple ligands driving Smad 2/3 and Smad1/5/8 signaling pathways that affect multiple cellular processes. We successfully utilized protein engineering to fine-tune the selectivity of the ActRIIB receptor. In this talk, we will discuss engineering and development of Luspatercept – a modified activin receptor type IIB Fc-fusion protein that acts as a TRAP for selective ligands of the TGF-beta superfamily involved in the late stages of erythropoiesis. We show that Luspatercept regulates late-stage erythrocyte precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoietin (EPO), which stimulates the proliferation of early-stage erythrocyte precursor cells.
11:20 Engineering Novel General Amyloid Interaction Motif (GAIM)-Immunoglobulin Fusions for Targeting Misfolded Protein Aggregates in Neurodegenerative Diseases
Ming Proschitsky, Ph.D., Senior Scientist, Research, Proclara Biosciences
The tip protein g3p of the filamentous bacteriophage M13 was previously identified as a General Amyloid Interaction Motif (GAIM) that binds and remodels a variety of fibrillar, amyloidogenic aggregates in a conformation-dependent manner. To prolong the half-life of this molecule in the blood, we genetically fused GAIM with a human immunoglobulin (hIgG1Fc). The fusion protein, currently in a Phase Ib clinical trial, displays 2 copies of GAIM, retains binding and remodeling activities towards amyloid fibrils in vitro and ex vivo.
11:50 New Strategies for Immunotherapy
Steven Almo, Ph.D., Chairman, Biochemistry, and Professor, Biochemistry and Physiology & Biophysics, Montefiore Medical Center, Albert Einstein College of Medicine
We describe a novel platform for the clonal specific expansion of disease-relevant T cells. Our approach manipulates antigen-specific (i.e., clonal) lymphocyte populations by covalently linking single chain peptide-MHC (sc-pMHC) and costimulatory molecules in a manner that recapitulates the proximity, orientation and overall organization experienced at the immunological synapse. These constructs are generated as Fc-fusion proteins (i.e. IgG) for enhanced avidity and stability. This combined targeting modulation construct is referred to as synTac (artificial immunological Synapse for T-cell Activation).
12:20 pm Luncheon Presentation: Tailor Made Sortases for Site Specific Bioconjugation
Mara Boenitz-Dulat, Ph.D., Head, Enzyme Development, Roche Diagnostics
We present a new type of sortase assay applicable as a high throughput screening tool and a very sensitive analytical method. Screening alternatives to generate new sortase variants by protein engineering and molecular dynamics simulations of engineered Sa-SrtA variant with substrate binding interactions will be discussed.
1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
Stefan Schmidt, Ph.D., M.B.A., Vice President, Process Science and Production, Rentschler Biotechnology
2:05 Fusion of Centyrin Scaffold Proteins to Engineered Albumin Binding Domains Allows for Tunable Pharmacokinetics
Shalom Goldberg, Ph.D., Senior Scientist, Johnson & Johnson
Targeted delivery of therapeutic payloads to specific tissues is an important component of modern pharmaceutical development. Antibodies or other scaffold proteins can provide the cellular address for delivering a covalently linked payload. Optimization of bioconjugate properties and exposure profile are important components on the path to developing a therapeutic candidate. This presentation will focus on current efforts to optimize Centyrins for payload delivery.
2:35 A Human Serum Albumin Domain I Fusion Protein for Antibody Conjugation
James Patterson, Ph.D., Senior Scientist, Project Leader, Antibody Technologies and Chemical Biology, Sorrento Therapeutics, Inc.
Bioorthogonal labeling of antibodies enables the conjugation of compounds to expand targeting capacity or enhance cytotoxicity. Taking advantage of a cyclohexene sulfonamide compound that site-selectively labels Lys64 in human serum albumin (HSA), we demonstrate that domain I of HSA can be used as a fusion protein for the preparation of serum-stable antibody conjugates. Conjugation via HSA domain I fusion should therefore have broad utility for making antibody conjugates.
3:05 The Potential of Veltis® Engineered Albumins for Optimized Drug Dosing
Joanna Hay, Ph.D., Science Manager, Customer Solution, Albumedix Ltd.
Albumin has been used for decades to enhance the pharmacokinetic and pharmacodynamic properties of drug candidates. We will describe rationally engineered albumins that further enhance these properties; variants with modified affinity to FcRn offer more than double the half-life extension to a drug candidate compared to that achieved with native albumin. We also present new engineered albumin variants with additional free thiol groups that allow multi-valent site specific drug loading.
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing
4:25 Multivalent Antibody-TRAIL Fusion Proteins for Cancer Therapy
Oliver Seifert, Ph.D., Post-Doc, Institute of Cell Biology and Immunology, University of Stuttgart
Engineering of multivalent antibody-scTRAIL (single-chain derivatives of TRAIL) by introducing different homodimerization modules leads to a novel platform of therapeutic molecules for cancer therapy. Our results show that both tumor targeting and enhancing the valency of scTRAIL fusion protein provides enforced apoptosis induction together with good anti-tumoral activity and tolerance in vivo. Due to the modular composition of this novel platform, exchanging the specificity of the antibody moiety facilitates the treatment of a broad spectrum of different cancer entities.
4:55 Functional Characterization of Mesothelin-Targeted TR3 Connects Translational Cancer Research with Fundamental Concepts of Native TRAIL Biology
Dirk Spitzer, Ph.D., Assistant Professor, Surgery, Washington University School of Medicine
The newly designed, genetically stabilized and constitutively trimerized TRAIL-based fusion protein TR3 has tremendous potential as a cancer therapeutic due to the possibility of creating biomarker-targeted variants under strict stoichiometric control. A detailed characterization of the improved activity profile of mesothelin-targeted scFv-TR3 revealed unexpected drug properties, which resulted in a better understanding of targeted drug design but also offered new insight into the ligand/receptor biology of the native TRAIL cytokine.
5:25 End of Fusion Protein Therapeutics
5:30 Registration for Dinner Short Courses
Recommended Dinner Short Course*
SC11: Overcoming the Challenges of Immunogenicity Assays, Risk Assessment and Meeting Regulatory Requirements - Detailed Agenda
*Separate registration required