Cambridge Healthtech Institute’s 12th Annual
Recombinant Protein Therapeutics
Fusion Proteins and Beyond
January 18-19, 2016
Cambridge Healthtech Institute’s Recombinant Protein Therapeutics conference explores the customizable functionality of fusion protein therapeutics, which possess 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. This meeting explores the varying constructs and “designs” of fusion
protein molecules, and discloses how these proteins are being engineered to form more efficacious therapeutics that offer specificity with enhanced stability and longer half-life.
MONDAY, JANUARY 18
7:30 am Conference Registration and Morning Coffee
9:00 Chairperson’s Opening Remarks
Stefan Schmidt, Ph.D., MBA, Vice President, Process Science and Production, Rentschler Biotechnology
9:10 Blood-Brain Barrier Penetrating IgG-Fusion Proteins for the Treatment of Lysosomal Storage Disorders
Ruben Boado, Ph.D., Vice President, R&D, ArmaGen, Inc.
Lysosomal enzymes, such as iduronase (IDUA) and sulfatases, are large molecule drugs that do not cross the blood-brain barrier (BBB). The BBB penetration of enzyme therapeutics is enabled by re-engineering the recombinant enzyme as IgG fusion
proteins, wherein the IgG transport domain targets a specific endogenous receptor-mediated transporter within the BBB, such as the human insulin receptor (HIR). First-in-human clinical trials are in progress.
9:50 Drug Delivery and Immunotherapy Enabled by a Tumor-Targeting Peptide-Fc Fusion
Jennifer Cochran, Ph.D., The Hitachi America Associate Professor, Bioengineering, and Chemical Engineering
Director, Graduate Studies, Stanford University
I will discuss an engineered peptide-Fc fusion protein that we have adapted for targeted delivery of chemotherapeutic agents, as well as recruitment of immune cell effector functions to tumors. The co-administration of peptide-Fc fusion and an
immune stimulating cytokine results in significant control of tumor growth in melanoma and colon carcinoma models, which is further enhanced by combination with checkpoint blockade inhibitors.
10:20 Coffee Break
⊲ Featured Presentation
10:45 Next-Generation FVIII Fusion Protein Incorporating Both XTEN Insertions and von Willebrand Factor
Robert Peters, Ph.D., Vice President, Hematology Research, Biogen
Clotting factor VIII (FVIII) normally associates with endogenous von Willebrand Factor (VWF), which stabilizes the protein and protects the clotting factor from clearance and proteolysis, but also appears to set an upper limit to the degree of
half-life extension achieved with Fc fusion or PEGylation technologies. We have engineered a fusion of FVIII to the D'D3 region of VWF through an Fc region and demonstrated that this provides intramolecular shielding from endogenous VWF, decoupling
the fusion protein from the VWF half-life extension limitations. Further incorporation of two XTEN insertions, unstructured hydrophilic protein polymers, have enabled us to extend the half-life of FVIII in hemophilia A mice to 2-fold beyond
that achieved with Fc fusion technology, and 4-fold beyond FVIII alone. The final rFVIIIFc-VWF-XTEN fusion protein has been engineered such that cleavage by thrombin, the physiological activator of FVIII, removes the VWF domains and XTEN insertions,
leaving the native activated FVIII as a simple Fc fusion that is able to interact normally with other proteins in the coagulation cascade, as demonstrated in both in vitro and in vivo models.
11:15 Development of Luspatercept as a Therapeutic for Anemia Caused by Ineffective Erythropoiesis
Ravindra Kumar, Ph.D., CSO, Acceleron Pharma, Inc.
Several members of the TGFb superfamily such as activins, GDF11 regulate gene transcription thru Smad2/3 phosphorylation. Increased Smad2/3 phosphorylation has been observed in
diseases of anemia caused by ineffective erythropoiesis such as thalassemia and myelodysplastic syndrome (MDS). We have developed luspatercept (ACE-536) as a trap for selective ligands responsible for Smad2/3 activation. Murine ortholog of
ACE-536 (RAP-536) has been shown to enhance differentiation of late stage erythroblasts and attenuate ineffective erythropoiesis. We will show the effect of RAP-536 treatment to correct anemia in murine model of thalassemia and MDS.
11:45 Development of Physiocrine-Based Therapeutics
Andrew Cubitt, Ph.D., Vice President, Intellectual Property, aTyr Pharma, Inc.
Physiocrines are extracellular signaling regions of tRNA synthetases, enzymes that catalyze a key step in protein synthesis, and act as endogenous modulators of the immune system. Physiocrines offer the opportunity to modulate biological pathways
through naturally occurring mechanisms that provide advantages including reduced side effects. Our product, Resokine IV, is in Phase I clinical trials, and is a therapeutic for rare disorders where a patient’s immune system is imbalanced.
12:15 pm Sponsored Presentation (Opportunity Available)
12:45 Session Break
1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
2:00 Chairperson’s Remarks
Céline Monnet, Ph.D., Senior Scientist, Molecular Design Unit, Innovation Department, LFB Biotechnologies
2:05 Targeting MUC16-Positive Malignancies with the Novel TRAIL-Based Cancer Therapeutic Meso64-TR3
Dirk Spitzer, Ph.D., Instructor, Surgery, Washington University School of Medicine
We recently redesigned the way the soluble TNF superfamily member TRAIL can be produced from mammalian cells by creating a head-to-tail fusion protein (trimer), designated TR3. This new drug platform has great potential as a cancer therapeutic
due to its extensibility with the goal of creating tumor-targeted TR3 analogs in a stoichiometrically controlled fashion. Here, we will present our latest data on the second generation, MUC16 (CA125)-targeted biologic Meso64-TR3.
2:35 Potential Role of LEC/Antibody Fusion Protein in the Immunotherapy of Cancer
Alan L. Epstein, M.D., Ph.D., Professor, Pathology, University of Southern California Keck School of
A novel fusion protein consisting of the human chemokine LEC and a human antibody that targets degenerative regions of tumors has been found to be an effective reagent for the immunotherapy of cancer. Used with inhibitors of tumor-induced
immunosuppression, experimental tumors show dramatic regression after IV treatment. Due to its broad applicability and unique mechanism of action, this reagent has high potential in enhancing current immunotherapy approaches and vaccine
3:05 Engaging Innate and Adaptive Immunity Using Cancer-Reactive Immunocytokines
Paul M. Sondel, M.D., Ph.D., Professor, Pediatrics, Hematology & Oncology, University of Wisconsin,
Ideal cancer therapy should be tumor-specific, eradicate primary tumors and metastases and prevent recurrence. Our research team has used tumor-reactive mAbs linked to IL2 (immunocytokines) as an initial platform to induce innate and adaptive
anti-tumor effects. Effective preclinical approaches have moved into clinical testing. We are now testing immunotherapies in combination; our goal is to identify and refine combinations of “off the shelf” immunotherapies
that can eliminate cancer.
3:35 SELECTED POSTER PRESENTATION
Thermally Responsive TRAIL Receptor Agonist Fusions are Potent Cancer Therapeutics
Mandana Manzari, Ph.D. Candidate, Biomedical Engineering, Duke University
3:50 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Affibody-Based C5 Inhibitors for Targeting the Terminal Complement Pathway
Patrik Strömberg, Ph.D., MBA, Senior Director and Head, Biomedical Science &
Portfolio Innovation, Swedish Orphan Biovitrum AB (SOBI)
Complement inhibitors against C5 have been developed utilizing the innovative Affibody scaffold for protein targeting. In order to optimize and “tailor” the PK/PD properties for leads in different applications, various
fusion protein and protein engineering approaches were tested. In this talk, data from several fusion proteins and PEGylated molecules will be described.
5:00 Proinsulin-Transferrin Fusion Protein as a Long-Lasting and Liver-Targeted Insulin Analog
Wei-Chiang Shen, Ph.D., John A. Biles Professor, Pharmacology & Pharmaceutical Sciences,
University of Southern California
Liver-specific insulin action is important in insulin therapy due to physiological relevance. A fusion protein (ProINS-Tf) consisting of proinsulin (ProINS) and transferrin (Tf) was prepared. The liver-targeted effect is due to: Tf
receptor-mediated endocytosis, intracellular activation of ProINS-Tf, and long retention of the activated form in hepatocytes. In Type 1 diabetes mice, ProINS-Tf demonstrated: a long-lasting glucose lowering effect, no peripheral
insulin action, and no severe hypoglycemia at high doses.
Welcome Reception in the Exhibit Hall with Poster Viewing
7:45 Close of Day
TUESDAY, JANUARY 19
8:00 am Conference Registration and Morning Coffee
8:30 Chairperson’s Remarks
Wei-Chiang Shen, Ph.D., John A. Biles Professor, Pharmacology & Pharmaceutical Sciences, University of Southern California
8:35 Fc Engineering to Increase Half-Life and Reduce Effector Functions
Céline Monnet, Ph.D., Senior Scientist, Molecular Design Unit, Innovation Department,
Using random mutagenesis and phage display technologies, we have isolated several Fc variants of human IgG1 with improved affinity for the neonatal Fc receptor (FcRn). These Fc variants allow for increased serum persistence in
human FcRn-transgenic mice. Their binding capacities to complement and FcgRs are variably affected. The variant with the longest half-life proved devoid of effector functions and could be used to improve therapeutic Fc fusion
9:05 Affibody-Based Ligand-Trap that Blocks IL-17 with Unparalleled in vivo Potency and Long Plasma Half-Life
Joachim Feldwisch, Ph.D., Director, Preclinical Development, Affibody AB
Il-17 is a potent inducer of tissue inflammation involved in auto-inflammatory disease. Here we describe the engineering of a ligand trap fusion protein designed to block IL-17 mediated pathology. The ligand trap is based on two
small Affibody scaffold domains for IL-17 inhibition, and an albumin binding domain for extended plasma half-life supporting once monthly dosing. The fusion protein has unparalleled potency with complete blocking of the dimeric
9:35 SELECTED POSTER PRESENTATION
Selection and Optimization of a scFv as a Targeting Ligand for a Cytotoxic Nanoparticle
Kathy Zhang, M.D., Scientist, Merrimack Pharmaceuticals
9:50 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 Targeting Therapeutics with an Antibody Specific to Damaged Arthritic Cartilage
Ahuva Nissim, Ph.D., Reader, Antibody and
Therapeutic Engineering, Biochemical Pharmacology, Queen Mary University
Our study demonstrates an antibody that binds specifically to arthritic cartilage enhanced therapeutic efficacy of murine tumor necrosis factor receptor 2-Fc (mTNFR2-Fc, a mouse version of Etanercept) and viral-IL-10 (vIL-10). Our platform technology is novel and combines several approaches to achieve what no existing treatment can do: a drug can be injected systemically, localize specifically to arthritic joints, remain there and release its therapeutic payload in response to disease activity.
11:30 Manufacturing Recombinant Protein Therapeutics under Cost Constraints
Stefan Schmidt, Ph.D., MBA, Vice President, Process Science and Production,
Biologicals represent the fastest growing segment in the drug pipeline, which puts pressure on economical manufacturing. Here I demonstrate how to solve challenges by applying disposables, using modular concepts, scaling
up of perfusion processes, replacing costly affinity resins and reducing the number of steps in platform processes. With examples from fusion proteins to biosimilars, the case studies highlight successful process
design, optimization strategies, and critical manufacturing parameters.
12:00 pm Veltis® Technology: Engineered Albumins for Optimized Serum Half-Life Extension
Darrell Sleep, Director, Novozymes Biopharma R&D
Short circulatory half-life represents a major obstacle for many protein and peptide-based therapeutics, resulting in increased dosing with the consequent risk of side effects and reduced patient compliance. The half-life
of therapeutic can be significantly improved by conjugation or fusion to albumin, improved half-life is a result of increased size and recycling via the neonatal Fc receptor (FcRn). We will describe rationally engineered
albumins with increased FcRn affinity, and their application to improve the pharmacokinetic properties of therapeutic candidates, along with a new transgenic rodent model to aid the preclinical development of albumin-based
12:30 Session Break
12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:45 Close of Conference