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 Recombinant Protein Therapeutics conference explores the varying constructs and “designs” of fusion protein molecules, and discloses how they are being engineered to form more efficacious therapeutics that offer specificity with enhanced stability and longer half life. Experts present case studies from R&D through clinical data and share the results they have achieved.
Prophylactic clotting factor replacement in patients with hemophilia improves outcomes, but requires frequent injections with traditional therapies. Recombinant fusion of the Fc domain of human IgG with clotting factors VIII and IX was performed to extend the half-life of these factors and provide the potential to reduce the frequency of injections needed to control bleeding in hemophilia A and B patients, respectively. The Fc fusion factors are configured with monomeric factor VIII or IX covalently linked to dimeric Fc. These protein fusion products have recently been approved for the treatment of hemophilia and the development programs will be discussed.
10:20 Coffee Break
10:45 A Small Biologic Alternative to PCSK9 Antibodies: Pharmacologic Profile and Demonstration of Robust LDL Lowering with an Anti-PCSK9 Adnectin
Tracy Mitchell, Ph.D., Principal Scientist and Group Leader, Biomolecular Characterization, Bristol Myers-Squibb Co.
PCSK9 is perhaps the most promising drug target for treating cardiovascular disease since the discovery of statins. Compared with therapeutic IgG antibodies currently in clinical trials, targeting circulating PCSK9 with a smaller molecular scaffold could offer reduced dose burdens and different pharmacologic profiles. We present the pharmacological profile of BMS-962476, a potent Adnectin inhibitor of PCSK9 that has demonstrated robust target engagement and LDL lowering in mice, cynos and humans.
11:15 Development of an Intein-Based Conjugation Platform for the Synthesis of Fc-Fusion Proteins
Oliver Thiel, Ph.D., Principal Scientist, Chemical Process Research & Development, Amgen, Inc.
Identification of an ideal platform technology for conjugation of small molecules and peptides to biomolecules for improved pharmacokinetics has been a recent focus within academic and industrial laboratories. This contribution will focus on the development of an intein-based platform for conjugation of peptides at the C-terminus of the Fc domain of immunoglobulins. In the course of platform development, selection of intein, cleavage residue, and linker between Fc and intein were examined.
11:45 A Bi-Functional Antibody-Receptor Domain Fusion Protein Simultaneously Targeting IGF-IR and VEGF for Degradation
Yang Shen, Ph.D., Research Advisor, Antibody Engineering, Eli Lilly & Company
A fully human Bi-functional Antibody-receptor domain (VEGFR1 domain 2) fusion molecule with ligand Capture (BiAbCap) targeting IGF-IR and VEGF was designed and developed, that displays excellent thermal and physical stability. Taking advantage of natural receptor-ligand interaction, bi-AbCap represents a novel and developable format of bi-functional antibodies with potent neutralizing activities against both targets. The unique “capture-for-degradation” mechanism translates to potent anti-tumor activity superior to the combination in vivo.
12:15 pm Reinventing Immunoassays: Introducing the Simple ELISA
Rajiv Pande, Ph.D., ProteinSimple
Although ELISA is routinely used for measuring individual protein analytes it has limitations in translational research applications where precise and accurate analysis of multiple analytes from small
sample volumes is required. ProteinSimple has developed the Simple Plex, a fully automated, hands-free immunoassay platform that retains the specificity of single-analyte ELISAs, but provides rapid multi-analyte analysis. The Simple Plex integrates a desktop analyzer with a disposable microfluidic cartridge to deliver superior performance and unprecedented ease of use in research and diagnostic applications.
12:45 Session Break
1:00 LUNCHEON PRESENTATION:
Applications of Acoustic Membrane Micro Particle in Large Molecule Bioanalysis
Johanna Mora, Ph.D., Senior Research Investigator II, 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 PK determination of a domain antibody and cover results on accuracy and precision and selectivity assessments. The second case study will cover the development of an immunogenicity assay on the AMMP where none of the established platforms were able to achieve adequate sensitivity.
2:00 Chairperson’s Remarks
Manfred Schuster, Ph.D., COO, Apeiron Biologics AG
2:05 Unravelling the Molecular Basis of Host Cell-Specific Glycosylation and Species-Specific Pharmacokinetics
Catherine Huntington, Ph.D., Research Scientist II, Antibody Discovery and Protein Engineering (ADPE), MedImmune, LLC
Glycosylation plays a significant role in the half-life of recombinant proteins in vivo, with the production cell lines affecting PK. Here, we expand on observations that HEK-293 expressed proteins are rapidly cleared in mouse models and our efforts to characterise the glycan forms responsible. Additionally, we will present our work to develop methods to profile glycan forms on recombinant proteins with the aim to predict impact on half-life of different species.
2:35 Enhancing Stability of the Therapeutic Enzyme L-Asparaginase by Biocompatible Nanoparticles
Manfred Konrad, Ph.D., Research Director, Enzyme Biochemistry, Max Planck Institute for Biophysical Chemistry
The enzyme L-asparaginase is a protein drug of high value in antileukemic therapy. Clinically approved L-asparaginases are of bacterial origin, though they elicit severe side effects, in particular immunogenicity. We present a novel approach for encapsulation of the enzyme using calcium carbonate particles surrounded by layers of biocompatible polymers, thus forming nanocontainers as carriers to enhance serum stability and suppress recognition by the immune system.
3:05 Manufacturing of Half-Life Extended Fusion Proteins: Current Trends and Challenges
Stefan Schmidt, Ph.D., Vice President, DSP, Rentschler Biotechnology
Second and third generation therapeutic proteins often contain a half-life extension moiety. These additional modules of fusion proteins often complicate the manufacturing process as they require specific adaptations of both up- and downstream processes. First, we give a comprehensive overview on the current state-of-the-art regarding half-life extension technologies, and second, we illustrate manufacturing challenges and solutions presented through selected case studies, additionally giving practical advice on optimization potential.
3:35 Sponsored Presentation (Opportunity Available)
3:50 Refreshment Break
4:15 A Neuroprotective Brain-Penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis
Eliezer Masliah, M.D., Professor, Neuroscience and Pathology, University of California at San Diego
Alzheimer’s (AD) and Parkinson’s Disease (PD) are the most common neurodegenerative disorders. We developed recombinant endopeptidases and antibodies with a unique brain targeting sequence derived from ApoB and have shown in animal models of AD and PD that these hybrid proteins ameliorate the pathology and recover the functional deficits. These results suggest that the recombinant brain-targeted proteins might be of use in the treatment of AD and PD.
4:45 Novel Human Resistant Mutant that Acts as Antagonist Reduced Body Weight Gain and Restored Insulin Responsiveness in Mice Fed High Fat Diet
Arieh Gertler, Ph.D., CEO, Protein Laboratories Rehovot; Professor-Emeritus and Head of Research Team, Biochemistry, The Hebrew University of Jerusalem
Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. To block resistin action, we developed a recombinant human resistin mutant (C6A) that acts as a resistin antagonist (RA). We clearly show that RA leads to a significant decrease in body weight of HFD mice. Importantly, RA treatment completely restored glucose tolerance as evidenced by glucose tolerance test and also restored insulin-responsiveness as estimated by insulin tolerance test.
5:15 Local Inhibition of Cytokine Signaling to Treat Anterior and Posterior Ocular Disorders
Eric Furfine, Ph.D., CSO, Eleven Biotherapeutics
Cytokines, chemokines, and growth factors mediate anterior and posterior eye diseases. Our lead product, the IL-1 receptor inhibitor EBI-005, was designed and engineered for the topical treatment of dry eye disease and was biologically active in subjects with dry eye disease. In addition, we engineered an IL-6 inhibitor with potential for local treatment diabetic macular edema. Finally, a novel soluble receptor inhibitor of cytokines IL-17A and IL-17F was engineered for the local treatment of uveitis. Both IL-6- and IL-17-targeted drugs were designed and engineered for intravitreal administration.
5:45-7:00 Welcome Reception in the Exhibit Hall with Poster Viewing
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