Fusion Protein Therapeutics

 

Chimeric fusion proteins, with their ability to extend plasma half-life and prolong therapeutic activity, offer exciting benefits over antibody-based therapeutics. Companies are intensely investigating into fusion protein therapeutics as a promising alternative to antibodies. The 5th Annual Fusion Protein Therapeutics will explore the latest developments and future prospects of this exciting modality by inviting researchers to present their novel Fc-fusion platforms, present updates from preclinical and clinical trials, and discuss engineering and conjugation strategies to improve efficacy, safety and clinical success.

Final Agenda

MONDAY, APRIL 8

7:00 am Registration (Commonwealth Hall) and Morning Coffee (Harbor Level)

NOVEL FORMATS AND APPLICATIONS

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8:30 Chairperson’s Opening Remarks

Celine Monnet, PhD, Head of Laboratory, Research, LFB Biotechnologies

8:40 Antibody-Cytokine Fusion Proteins: From Discovery to Pivotal Clinical Trials

Neri_DarioDario Neri, PhD, Professor, Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich)

Antibody-cytokine fusions allow to concentrate immunomodulatory activities at the site of disease, helping spare normal tissues. I will present preclinical and clinical work, conducted in collaboration between my laboratory at ETH Zürich and Philogen in the field of cancer and of chronic inflammation.

9:10 Novel Fc Platform Development and Application for Fc-Fusion Proteins

Shan_LuLu Shan, PhD, Scientist II, ADPE, MedImmune


Monovalent fusion proteins are often a necessary drug format for optimal structure and activity profiles. We present our novel monovalent fusion platform in target validation and lead discovery.

9:40 Redefinition of RTK Tumor Targeting: How to Design Truly Potent anti-ErbB Bispecific and Biparatopic Fusion Therapeutics

Tamaskovic_RastislavRastislav Tamaskovic, PhD, Head, TC Facility, Biochemistry, University of Zurich

Recently, we have described major compensatory routes, which become activated in therapy of HER2-positive cancer, and developed a new class of bispecific and biparatopic anti-ErbB/Met/Axl fusion protein agents endowed with capabilities to overcome the adaptive resistance. These novel targeting vehicles achieve their superior tumoricidal activity by trapping tumor-driving receptor tyrosine kinases in inactive conformations and/or supramolecular assemblies. Analogously, we build a new platform for tumor RTK fingerprinting aimed at identifying prospective therapeutic leads and truly synergistic combination therapies.

10:10 Networking Coffee Break (Harbor & Mezzanine Level)


10:50 KEYNOTE PRESENTATION: Preconditioning the Tumor Microenvironment to Enable Effective Immunotherapy Using Antibody Fusion Proteins

Epstein_AlanAlan Epstein, MD, PhD, Professor, Keck School of Medicine, University of Southern California

In the last 10 years, my laboratory has explored the potential of antibody fusion proteins consisting of cytokines, chemokines, and co-stimulatory molecules to alter the tumor microenvironment as a new direction of cancer immunotherapy. In addition to targeting adaptive immunity, the laboratory is currently exploring the potential application of targeted innate immunity using toll-like receptor agonists chemically linked to tumor targeting antibodies. In addition, biobetter checkpoint inhibitors are being prepared that alter immunodominant pathways required for successful immunotherapy.

11:20 Leveraging FcRn-Blocking Therapeutic Utility for Autoantibody Mediated Disease through a Minimized Affibody Fusion Format

Frejd_FredrikFredrik Frejd, PhD, CSO, Affibody AB

Several diseases are mediated by autoantibodies. Reduction of antibody plasma levels by pharmacologic interference with the neonatal FcRn receptor can reduce disease burden and save lives. Antibodies are suboptimal drugs as they rely on FcRn for long plasma half-life. ABY-039 is an FcRn blocking affibody molecule that overcomes limitations of antibody-based approaches to achieve very long half-life and outpatient subcutaneous administration. Engineering, development and clinical data will be presented.

11:50 Antibody-Targeted Superantigens and Antibody Directed Enzyme Prodrug Therapy for Improved Safety and Efficacy for Cancer Treatment

Goda_SayedSayed Goda, PhD, Professor, Senior Scientist, Anti-Doping Lab Qatar, Cairo University

I will present novel data for cancer treatment using Antibody Directed Enzyme Prodrug Therapy (ADEPT) and Tumor Targeted Superantigens (TTS). For ADEPT, we successfully produced an ultra-active glucarpidase that degrades MTX with a very high efficiency, and produced novel fusion with our newly discovered enzyme for targeted cancer therapy. For TTS, we successfully produced truncated superantigens with much less lethality; and novel variants of superantigens with less toxicity. We are developing cancer specific antibody-superantigen fragment fusion complex for further study.

12:20 pm Utilizing Fusion Platforms for the Development of Efficient Hemin Scavengers Towards Therapeutic Use in Sickle Cell Disease and Other Hemolytic Disorders

Karnaukhova_ElenaElena Karnaukhova, PhD, Research Scientist, Laboratory of Biochemistry and Vascular BIology, CBER, US FDA

Detrimental effects of extracellular hemin released from hemoglobin are critically involved in hemolytic disorders. In the US alone, more than 100,000 people have homozygous sickle cell disease, however, currently there is no treatment to prevent or minimize the adverse consequences induced by the hemin release. This presentation focuses on the biophysical evaluation of hemin scavengers, utilizing fusion platforms, in collaboration with our colleagues from CSL Limited, Bio21 Institute, Parkville, Australia and University Hospital of Zurich, Switzerland.

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:50 Session Break

2:20 Problem-Solving Breakout Discussions - Click here for details (Commonwealth Hall)

3:20 Networking Refreshment Break (Harbor & Mezzanine Level)

PLENARY KEYNOTE SESSION

amphitheater & harborview ballroom

4:00 Chairperson’s Remarks

Rakesh Dixit, PhD, DABT, Vice President, R&D, Global Head, Biologics Safety Assessment, Translational Sciences, MedImmune

PLENARY KEYNOTE SPEAKER

4:10 Vision for How Immunotherapy Will Shape Future of Cancer Care

Leena-GandhiLeena Gandhi, MD, PhD, Vice President, Immuno-Oncology Medical Development, Lilly Oncology

Immunotherapy is considered by many as a pillar of cancer care today, but in many ways we have only scratched the surface. Our knowledge and understanding of the complexities of immunotherapy and its mechanisms continue to evolve. The future of cancer care will be defined by our ability to systematically identify and implement opportunities for combination therapy to improve and standardize patient response.

YOUNG SCIENTIST KEYNOTE

4:55 The Lassa Virus Glycoprotein: Stopping a Moving Target

keynote-headshot-hastie-400x400Kathryn Hastie, PhD, Staff Scientist, Immunology and Microbiology, The Scripps Research Institute

Lassa virus causes ~5000 deaths from viral hemorrhagic fever every year in West Africa. The trimeric surface glycoprotein, termed GPC, is critical for infection, is the target for neutralizing antibodies, and a major component of vaccines. Structural analysis of Lassa GPC bound to antibodies from human survivors reveals a major Achilles heel for the virus and provides the needed template for development of immunotherapeutics and improved vaccines.

5:40 Welcome Reception in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

7:15 End of Day

TUESDAY, APRIL 9

8:00 am Registration (Commonwealth Hall) and Morning Coffee (Harbor Level)

ENGINEERING AND OPTIMIZATION OF FUSION PROTEINS

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8:25 Chairperson’s Remarks

Dario Neri, PhD, Professor, Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich)

8:30 Synergistic Cytotoxicity Promoted by Human Serum Albumin Fusion Protein and Fatty Acid-Modified 5-Fluorouracil

Zhiyu Li, PhD, Associate Professor of Pharmaceutical Sciences, Director, Pharmacology and Toxicology Undergraduate Program, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy

Human serum albumin and p53-derived peptide fusion protein (rHSA-p53i) and recombinant wild type albumin (rHSA) exhibited similar biodistributions in mice; however, rHSA-p53i accumulated much more in tumor tissue. This fusion protein could also induce cytotoxicity irrespective of p53 status and display synergistic cytotoxicity with 5-fluorouracil (5FU) in cancer cells. Therefore, fatty acid-modified 5FU (FA-5FU) was synthesized to form stable non-covalent complexes with rHSA-p53i. FA-5FU showed cytotoxicity comparable with that of 5FU and FA-5FU/rHSA-p53i complexes together achieved a profound synergistic anticancer efficacy in vitro and in vivo in SJSA-1 and MDA-MB-231 xenograft mouse models.

9:00 Fc Sialylation Prolongs Serum Half-Life of Therapeutic Antibodies

Monnet_CelineCeline Monnet, PhD, Head of Laboratory, Research, LFB Biotechnologies

We demonstrated a hitherto unrecognized impact of Fc hyper-sialylation of the Asparagine 297 on the prolongation of IgG1 serum persistence. The enhanced longevity was due to the sialylated sugar moiety itself and did not modify the binding affinity to the neonatal Fc receptor (FcRn). This polarized glycosylation is achieved using a novel Fc mutation, a glutamate-residue deletion at position 294 (Del) that endows therapeutic antibodies with an up to 9-fold increase in serum lifespan.

9:30 Potential Applications of A New Recombinant Protein Format: Self-Assembling Nanoclusters for Protein Delivery and Protein Purification Purposes

GarciaFruitos_ElenaElena Garcia Fruitós, PhD, Researcher, Ruminant Production, Institute of Agriculture and Food Research and Technology

The reduction of production costs and stability improvement of recombinant soluble proteins remains a challenge. In this scenario, we have been working on the development of a new protein format based on self-assembling nanoclusters as a promising alternative in terms of stability and slow release for protein delivery and protein purification purposes. For that, we are working with endotoxin-free expression systems such as Lactococcus lactis and Lactobacillus plantarum.

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

FUSION PROTEINS FOR NON-ONOLOGY INDICATIONS

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10:50 Next-Generation Antibody-Guided Enzyme Replacement Therapy for Lysosomal Diseases

Cygnar_KatherineKatherine Cygnar, PhD, Senior Staff Scientist, Genome Engineering Technologies, Regeneron Pharmaceuticals

Enzyme replacement therapy revolutionized treatment for lysosomal diseases, but many patients still show progressive disease on therapy mainly due to poor enzyme uptake in critical tissues. Here we show a fusion protein between the enzyme and an antibody binding an internalizing protein improves enzyme delivery to critical tissues, and completely/near-completely corrects disease phenotypes in a mouse model of Pompe disease. This platform is amenable to both protein therapeutics and gene therapy.

11:20 Platform Technology for Treatment of the Brain in Lysosomal Storage Disorders with IgG-Fusion Proteins: Preclinical and Clinical Update

Boado_RubenRuben Boado, PhD, Vice President, R&D and Co-Founder, ArmaGen, Inc.

Protein therapeutics can be re-engineered as brain penetrating IgG-fusion proteins for the CNS treatment of rare disorders, like Lysosomal Storage Disorders (LSD). The BBB-penetration of enzyme therapeutics is enabled by re-engineering the recombinant enzyme as bi-functional IgG fusion proteins. The enzyme therapeutic domain of the fusion protein exerts the pharmacological effect in brain once across the BBB. Several brain penetrating IgG-LSD fusion proteins have been engineered and validated. First-in-human POC Phase II clinical trial in LSD will be discussed.

11:50 Protein Engineering by Directed Evolution to Derive ALPN-101, a Dual ICOS/CD28 Antagonist ICOSL Variant Ig Domain (vIgD)-Fc Fusion Protein for the Treatment of Inflammatory Diseases

Rixon_MarkMark Rixon, PhD, Senior Director, Protein Therapeutics, Alpine Immune Sciences

ALPN-101 is an Fc fusion protein designed to inhibit simultaneously the CD28 and ICOS costimulatory pathways. Through directed evolution of the ICOSL extracellular variable Ig domains, Alpine Immune Sciences has engineered ALPN-101 to have increased affinity to the natural counter structure ICOS and gain of binding to the non-cognate ligand CD28. Preclinical data demonstrate superior in vitro and in vivo efficacy and corroborate the dual ICOS/CD28 antagonism of T cell costimulatory signaling.

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 (Commonwealth Hall)

FUSION PROTEINS AS IMMUNOTHERAPY AGENTS

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2:00 Chairperson’s Remarks

Alan Epstein, MD, PhD, Professor, Keck School of Medicine, University of Southern California

2:05 Engineering Hexavalent TNFR-SF Agonists for Cancer Immunotherapy: A Unique Class of Biologics

Hill_OliverOliver Hill, PhD, Vice President, Molecular Biology/Protein Engineering, Apogenix AG

Apogenix’s Hexavalent TNFR-SF agonist (HERA) is based on trivalent but single-chain molecular mimics of the TNF-SF receptor binding domains fused to a dimerization scaffold. The resulting hexavalent fusion proteins are potent TNFR-SF agonists that activate distinct immune cell populations involved in the anti-tumor immune reaction thereby enabling exciting opportunities for combination treatment with other I-O drugs. The engineering details and recent results obtained for HERA-CD40L, HERA-CD27L, and HERA-GITRL will be presented.

2:35 Development of a Novel Multi-Specific Antibody Targeting PD-L1-Overexpressing Cancers by Engagement of Antigen-Committed CD8+ T Cells via the Costimulatory Receptor 4-1BB

Meyer_SebastianSebastian Meyer, PhD, COO, Numab Innovation AG

Targeting PD-L1 and 4-1BB with a multi-specific antibody format holds the promise of increased potency while improving the safety profile compared to combination therapy. Numab develops a molecule that potently blocks PD-L1/PD-1 signaling and elicits further T cell activation through its costimulatory domain. Preclinical data show efficacy on tumor growth in combination with an enhanced intratumoral CD8+ T cell activation when compared to the combination of the PD-L1 and 4-1BB modalities.

3:05 IL-DR2 Fc Is a Novel Regulator of Immune Homeostasis and Inducer of Antigen-Specific Tolerance

Miller_StephenStephen D. Miller, PhD, Judy Gugenheim Research Professor, Director, Interdepartmental Immunobiology Center, Microbiology-Immunology, Northwestern University Medical School

ILDR2 is a member of the Ig superfamily and has a putative role in pancreatic islet health and survival. We recently found a novel role for ILDR2 in delivering inhibitory signals to T cells. ILDR2-Fc displays a unique mode of action, combining immunomodulation, regulation of immune homeostasis, and re-establishment of Ag-specific immune tolerance via induction of regulatory T cells. These findings support the potential of ILDR-Fc as a promising therapeutic approach for the treatment of autoimmune diseases.

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

IMPROVING CYTOPLASMIC DELIVERY AND Pk Properties

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4:25 The Evolving Science and Long-Term Outcomes of Fc Fusion Factors

Joe Salas, PhD, Executive Director, Protein Therapeutis, Bioverativ Inc.

 

4:55 POSTER HIGHLIGHT I: Cytoplasmic Delivery of Inhibitory Antibodies

Tsourkas_AndrewAndrew Tsourkas, PhD, Professor, Bioengineering, University of Pennsylvania

Antibodies can directly neutralize their antigen’s biological activity, but their inability to cross the plasma membrane has limited them to secreted or membrane-associated targets. We have developed a site-specific bioconjugation strategy that links anionic polypeptides to native IgGs, allowing them to be complexed with lipids and polymers originally developed for nucleic acid delivery. The resulting complexes can efficiently deliver antibodies that inhibit drug targets into the cytoplasm, demonstrating that cytoplasmic antibodies are a viable new class of therapeutics. 

5:10 POSTER HIGHLIGHT II: Utlizing Bioorthogonal Chemistry for Improving the Pharmacokinetic Properties and Inhibitory Potency of N-TIMP2

Hayun_HeziHezi Hayun, PhD, Biotechnology Engineering, Ben Gurion University

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that regulate the degradation of the extracellular matrix (ECM) components, in biological processes such as angiogenesis and wound healing. MMPs activity is regulated by natural Tissue Inhibitors of Metalloproteinases (TIMPs) that can inhibit MMP's activity, but some can also mediate activation of some pro-MMPs. Synthetic MMP inhibitors exhibit great inhibition by chelating the MMP catalytic Zn2+, but have some drawbacks such as poor pharmacokinetics and severe adverse effects, which limit their use as therapeutic drugs.Engineering approach showed that the N-terminal domain of TIMP-2 (N-TIMP2) is sufficient to inhibit MMPs activity, without leading to pro-MMP-2 activation. Thus, we have decided to use bioorthogonal chemistry to incorporate a non-canonical amino acid (NCAA) into N-TIMP2, allowing a site-specific PEGylation and a better control for this modification. We have managed to incorporate propargyl lysine (PrK) into N-TIMP2 in different positions. This residue is aimed to be conjugated with PEG-azide in a click chemistry reaction, followed by examination of the inhibition activity towards MMP-14 as well as the pharmacokinetic properties of the modified variants in in vitro and in vivo studies.    

5:25 End of Fusion Protein Therapeutics

5:30 Registration for Dinner Short Courses (Commonwealth Hall)


Recommended Dinner Short Course*

SC11: Developability of Bispecific Antibodies: Formats and Applications

Nimish Gera, PhD, Director, Research and Development, Mythic Therapeutics

 

*Separate registration required.

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