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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. This meeting 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.


MONDAY, MAY 4

7:00 am Registration and Morning Coffee


plenary keynote session

8:30 Chairperson’s Opening Plenary Remarks

8:40 Cancer Stem Cells and Mechanisms of Malignant Progression

Robert A. Weinberg, Ph.D., Founding Member, Whitehead Institute for Biomedical Research; Professor, Biology, Massachusetts Institute of Technology

The cell-biological program termed the epithelial-mesenchymal transition (EMT) plays a role in conferring aggressive traits on carcinoma cells. In addition, it generates cancer stem cells (CSCs) that have the ability, following dissemination, to serve as founders of new metastatic colonies. The relationship between these CSCs and the SCs residing in normal tissues, and the participation of the CSCs in metastatic dissemination will be described.

9:25 Building an Antibody Discovery Company in a Crowded Field – the Adimab Story

Tillman Gerngross, Ph.D., CEO, Co-Founder, Adimab

The presentation will cover the evolution of Adimab from its founding in 2007 to becoming one of the few privately held profitable biotech companies in the last decade. Industry trends and specific strategic decisions along the way will be discussed and used to illustrate the importance of integrating finance and scientific information to build successful capital efficient biotech companies.

10:10 Coffee Break


Achieving Success with Therapeutic Fusion Proteins

10:45 Chairperson’s Remarks

Fredrik Frejd, Ph.D., Chief Scientific Officer, Biotherapy, Affibody AB


10:50 KEYNOTE PRESENTATIONS

Engineering Clotting Factor Fc Fusion Proteins for the Treatment of Hemophilia

Jennifer DumontJennifer Dumont, Ph.D., Director, Medical Affairs, Biogen Idec, Inc.

Prophylactic clotting factor replacement in patients with hemophilia improves outcomes, but requires frequent injections with conventional therapies. Recombinant fusion of the Fc domain of human IgG1 with clotting factors VIII or IX was performed to extend the half-life of these factors and provide the potential to reduce the frequency of injections needed to control and prevent bleeding in hemophilia A and B patients, respectively. The Fc fusion factors are configured with monomeric factor VIII or IX covalently fused to dimeric Fc. These protein fusion products are now approved for the treatment of hemophilia and the development programs will be discussed.

11:20 Featured Presentation: 
Therapeutic Fusion Proteins: Current Trends and Challenges

Stefan SchmidtStefan Schmidt, Ph.D., Vice President, DSP, Rentschler Biotechnology

This talk examines the state-of-the-art in developing fusion proteins for biopharmaceuticals, shedding light on the immense potential inherent in fusion protein design and functionality. First, I will present a comprehensive overview on the current trends, and second, I will address challenges and how to overcome them.

11:50  Veltis® Technology: Engineered Albumins for Optimized Serum Half-Life Extension

Bunting_KarenKaren Bunting, Ph.D., Senior Research Scientist, Molecular Biology and Fermentation, Novozymes Biopharma UK

Short circulatory half-life represents a major obstacle for many protein and peptide-based therapeutic agents, resulting in increased dosing with the consequent risk of side effects and reduced patient compliance. Molecule half-life can be significantly improved by association, conjugation or fusion to albumin, due to both 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.

12:20 pm Luncheon Presentation I: Development of a Generic Anti-PEG Antibody Assay Using BioScale's Acoustic Membrane MicroParticle Technology

Shannon D. Chilewski, MSc, Research Scientist II, Analytical and Bioanalytical Development, Bristol-Myers Squibb

In cases where established technologies cannot deliver on the assay sensitivity requirements set by a specific drug development program, alternative platforms may need to be evaluated. This presentation will share a case study on the application of the Acoustic Membrane Micro Particle (AMMP) technology for the development of an immunogenicity assay on the AMMP where none of the established platforms were able to achieve adequate sensitivity.


12:50 Luncheon Presentation II (Sponsorship Opportunity Available)

1:20 Session Break


Engineering Enhanced Properties

1:50 Chairperson’s Remarks

Mark Distefano, Ph.D., Professor, Chemistry and Medicinal Chemistry, University of Minnesota

1:55 Featured Presentation: 
PASylation: The Preparation of Fusion Proteins with Extended Plasma Half-Life Based on a Biological Alternative to PEG 

Arne SkerraArne Skerra, Ph.D., Professor, Technische Universität Munich; Chief Scientific Officer, XL-protein GmbH

PASylation allows the simple genetic fusion (or chemical coupling) of a therapeutic protein or peptide with a voluminous hydrophilic polypeptide composed of Pro, Ala, and/or Ser to retard kidney filtration. PAS sequences show surprisingly similar biophysical properties to PEG but, in contrast, are biodegradable. PASylation has been successfully applied to antibody fragments, growth hormones, cytokines and other biologics; for example, PAS-leptin fusion proteins show much enhanced satiety effects in mice.

2:25 Re-Engineering Lysosomal Enzyme Therapeutics for the Brain as IgG Fusion Proteins that Penetrate the Blood-Brain Barrier

Ruben BoadoRuben Boado, Ph.D., Vice President, R&D, ArmaGen, Inc.

Lysosomal enzymes are large molecule drugs that do not cross the blood-brain barrier (BBB). However, 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). The therapeutic domain of the IgG fusion protein exerts the pharmacological effect in the brain once across the BBB.

2:55 Pathogenesis-Mediated Targeted Cytokine Delivery

Unpublished Data
Yuti Chernajovsky
Yuti Chernajovsky, Ph.D., FRCP, Emeritus Professor, Molecular Medicine, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry

I will describe how fusion proteins of the latency associated peptide (LAP) from TGFb with therapeutic cytokines can be used to safely increase the half life of cytokines, confer latency and, using matrix metalloproteinase activity found at sites of disease, specifically release the therapeutic moiety where needed without side effects. A case will be made in favor of the use of latent cytokines as compared to anti-cytokine antibodies due to their novel pharmacodynamic properties.

3:25 Affibody-Based Ligand-Trap that Block IL-17 with Unparalleled in vivo Potency and Long Plasma Half-Life

Fredrik FrejdFredrik Frejd, Ph.D., Chief Scientific Officer, Biotherapy, 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 interleukin.

3:55 Refreshment Break in the Exhibit Hall with Poster Viewing

4:35 Problem-Solving Breakout Discussions

Cancer Stem Cell Therapeutics

Moderator: Agamemnon A. Epenetos, Ph.D., Chairman, Trojan Technologies, Ltd.

There is increasing evidence supporting the concept that cancer is initiated and maintained by a population of cancer cells that have similarities to normal adult stem cells, the cancer stem cell (CSC) hypothesis. Although the concept of CSCs is not new, progress made over the past two decades in our understanding of stem cell biology has resulted in the identification of CSCs in several human cancers.

  • Do CSCs exist, and if so, how important are they?
  • How do we detect them in vitro and in vivo?
  • Are they treatable or are they too similar to normal adult stem cells?
  • If treatable, what’s the best approach ?

Anti-Cytokine Antibodies vs. Targeted Cytokines. Which is the Best Therapeutic?

Moderator: Yuti Chernajovsky, Ph.D., FRCP, Emeritus Professor, Molecular Medicine, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry

Anti-cytokine antibodies are a main tool for therapy of inflammatory conditions, in particular, arthritis. Anti-TNF has changed the way rheumatoid arthritis is treated and changed the outcome for many patients who may become disease free. However, 60% of patients do not respond to anti-TNF, and drug administration has to be stopped in certain conditions due to its indiscriminate immunosuppressive effect. Anti-cytokine antibodies block cytokine action but do not block cytokine production. There are ways to stop cytokine production, for example using antagonistic cytokines e.g., Th2 cytokines control Th1 cytokine production. 

In this discussion group, we will address the pros and cons of targeted cytokines vs. anti-cytokine antibodies.

  • Pharmacokinetic and pharmacodynamic properties of anticytokine antibodies and targeted cytokines
  • Possible uses of targeted cytokines
  • Methods for improving targeting

Structure Activity Relationships for Immunoglobulin Fusion Proteins

Moderator: Richard A. Fisher, Ph.D., Chief Scientific Officer, NeuroPhage Pharmaceuticals

The creation of immunoglobulin fusions, which consist of an Fc fragment fused to a binding domain(s) generally impart longer half-life and bivalence with increased avidity for the targeting domain. These constructs can present several types of structure activity problems. The discussion will be around sharing experiences with these and other issues that affect "drug-ability".

  • Expression
  • Stability
  • Loss or gain of function to the binding domain
  • Immunogenicity

 

Pall Life Sciences_Fortebio

5:35 Welcome Reception in the Exhibit Hall with Poster Viewing

6:50 End of Day

TUESDAY, MAY 5

8:00 am Morning Coffee


Strategies for Engineering Fusion Protein Therapeutics

8:25 Chairperson’s Remarks

Stefan Schmidt, Ph.D., Vice President, DSP, Rentschler Biotechnology

8:30 Enzymatic Assembly of Fusion Proteins

Mark DistefanoMark Distefano, Ph.D., Professor, Chemistry and Medicinal Chemistry, University of Minnesota

Fusion proteins prepared by linking domains manifesting different functions have enormous potential for biomedical applications. Chemoenzymatic methods involving the enzymatic incorporation of chemical linkers coupled with bioorthogonal reactions greatly increase the repertoire of possible constructs that can be obtained. This presentation will focus on various protein fusions and assemblies that have been prepared using enzymatic modification with farnesyltransferase and subsequent chemical ligation.

9:00 Development of Affibody® C5 Inhibitors for Versatile and Efficient Therapeutic Targeting of the Terminal Complement Pathway

Patrik StrömbergPatrik Strömberg, Ph.D., Project Leader, R&D; Principal Scientist, Nonclinical Safety and Pharmacology, Swedish Orphan Biovitrum AB (SOBI)

We are developing protein therapeutics against complement component C5, utilizing the innovative Affibody scaffold for protein targeting. During lead generation and optimization, large efforts were made to optimize PK/PD properties, i.e., maximizing the plasma persistence of this small protein while maintaining inhibitory potency. In particular, pioneering studies with a novel albumin binding domain (ABD) technology were performed that ultimately generated the first clinical candidate from this program.

9:30 Functional Assay Strategies for Bispecific Antibodies and Fusion Proteins

Unpublished Data
Jörg Moelleken
Jörg Moelleken, Ph.D., Senior Scientist, Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg

The increasing complexity of novel biotherapeutics comprising of bispecific antibodies and fusion proteins raise new challenges for functional characterization as compared to standard antibodies. Besides varying binding sides, additional biologically relevant aspects like bi-specificity must be addressed now. This presentation shows points to consider relevant from lead identification until lead characterization.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing


TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) Fusion Proteins

10:50 Leading TRAIL to the Clinic: Improving Pharmacokinetics, Identifying Sensitizers and Selecting Cancer Types

Unpublished DataXiangwei Wu, Ph.D., Associate Professor, Clinical Cancer Prevention, MD Anderson Cancer Center

Interest in TRAIL has increased following the observation that TRAIL can selectively kill a wide variety of human cancer cells without harm normal cells. However, results from clinical trials of TRAIL-based therapy are disappointing. We will describe our approaches in improving TRAIL’s performance by generating Fc fusion TRAIL, identifying best drugs to work with TRAIL, and selecting subpopulation of patients who may benefit from TRAIL-based therapy.

11:20 Hexavalent Agonists Targeting Receptors of the Tumor Necrosis Factor Superfamily

Unpublished Data
Oliver Hill
Oliver Hill, Ph.D., Vice President, Molecular Biology, APOGENIX GmbH

Apogenix has engineered TRAIL mimetics with three Apo2L/TRAIL protomer subsequences genetically fused into one polypeptide chain. This trivalent single-chain TRAIL-receptor-binding domain (scTRAIL-RBD) was fused to a mutated Fc-part of human IgG1 to create a hexavalent scTRAIL-RBD dimer (scTRAIL-RBD-Fc). The underlying engineering concept was successfully transferred to CD40-ligand (CD154), resulting in a hexavalent CD40-agonist (scCD40L-RBD-Fc) suitable for clinical development. We will present our results on both agonists and discuss their impact on the design of novel TNFR super-family targeting biologics.

11:50 Cancer Therapy with TR3, a Genetically Stabilized TRAIL-Based Drug Platform with Increased Activity, Stability, and Targeting Capabilities

Dirk SpitzerDirk Spitzer, Ph.D., Instructor in Surgery, Washington University School of Medicine

Soluble TRAIL has a tremendous potential as a cancer drug but cannot form bioactive trimers when produced from monomeric cDNAs in mammalian cells. We solved these limitations by designing a head-to-tail fusion protein, resulting in the constitutive TRAIL trimer TR3. This new drug platform is extremely versatile, since it is generically extensible in modular fashion, while the domain stoichiometry is strictly controlled. Here, we will emphasize the latest optimization strategies performed on our MUC16-targeted cancer drug Meso-TR3.

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available)
or Enjoy Lunch on Your Own

1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing


Antibody Fusions

2:00 Chairperson’s Remarks

Dirk Spitzer, Ph.D., Instructor in Surgery, Washington University School of Medicine

2:05 Potential Role of LEC/Antibody Fusion Protein in the Immunotherapy of Cancer

Alan EpsteinAlan L. Epstein, M.D., Ph.D., Professor, Pathology, University of Southern California Keck School of Medicine

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 technology.

2:35 Antibody-IFN Fusion – A Combination of ADC and Targeted Immunotherapy

Sanjay KhareSanjay D. Khare, Ph.D., President and CEO, ImmunGene, Inc.

ImmunGene’s proprietary technology empowers antibodies by genetically engineering them with the tumor cell-killing cytokines, thereby combining the exquisite specificity of antibodies with the potent cytotoxic effects of cytokines. Antibody-cytokine fusion proteins are designed to be inactive systemically (against healthy cells) at the therapeutic doses, but stable in the bloodstream while efficiently targeting and killing cancer cells. This approach spares non-targeted (healthy) cells and thus reduces many of the known toxic effects of systemically administered cytokines while greatly enhancing the anti-tumor activity of antibodies.

3:05 SELECTED POSTER PRESENTATION:
A19: Syringe Pump Infusion - How to Overcome Clinical Administration Challenges for Fusion Proteins and Bispecific Antibodies
Jonas Fast, Ph.D., Group Leader, Senior Scientist, Early-Stage Pharmaceutical Development & GLP Supplies, F. Hoffmann-La Roche Ltd.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


CONQUERING DISEASE

4:25 Cancer Stem Cell Therapeutics

Agamemnon EpenetosAgamemnon A. Epenetos, Ph.D., Chairman, Trojan Technologies, Ltd.

It is likely that cancer stem cells, (CSCs) may be a key reason for the failure of current therapies. The NOTCH pathway is an important pathway in cancer stem cells. We have generated a hybrid protein (TR4) which translocates into the nucleus, suppresses NOTCH and eliminates human tumor growth; along with microparticles (MPs) derived from mesenchymal cells loaded with microRNAS. These MPs can fuse with tumors and affect tumor growth.

4:55 Discovery and Development of Novel Ig-GAIM Fusion NPT088 for Alzheimer’s Disease

Case Study
Richard Fisher
Richard A. Fisher, Ph.D., Chief Scientific Officer, NeuroPhage Pharmaceuticals

NPT088 is an Ig fusion displaying two copies of the General Amyloid Interaction Motif (GAIM) that targets misfolded protein assemblies. GAIM activities include potent (nM) binding to multiple types of amyloid fibrils, inhibition of misfolded protein assembly, cytoprotection from oligomer mediated toxicity, and disruption of amyloid structure. NPT088 has been tested in transgenic disease models, and after systemic administration NPT088 mediates reduction of pathology and improvements in behavior and cognition.

5:25 End of Conference

5:30 Registration for Dinner Short Courses


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