Pharma-Bio Partnering Forum: Biologics Partnering
Cambridge Healthtech Institute’s Second Annual
Antibody and Protein Engineering
April 29-30, 2013
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7:45 am Registration and Morning Coffee
8:15 Chairperson’s Remarks
8:05 Deep Screening of the OMT OmniRat™ Repertoire Using CellSpot™ Single Cell Multiplexing
Larry Kauvar, Ph.D., Senior Vice President & CSO, Trellis Bioscience
CellSpot™ is a patented technology for deep screening of the native antibody repertoire. It uses digital microscopy to provide multiplexed antigen recognition at single cell resolution, enabling detection of very rare B cells. Typical screening campaigns examine >10 million memory B cells. We have used CellSpot to explore the native human repertoire of memory B cells obtained from antigen exposed donors to identify superlative mAbs to 4 viral targets: RSV, CMV, Influenza Group 1 and Group 2. To broaden our therapeutic discovery platform, we have used CellSpot to screen spleen cells from hyperimmunized OmniRats that express the human IgG variable domains on a rat Fc framework. Combining the OmniRat and CellSpot technologies thus offers an efficient route to sub-nanomolar affinity fully human mAbs that meet stringent specificity criteria. For targets outside the infectious disease arena, or for highly pathological emerging diseases, this combination holds considerable potential to identify superlative clinical candidates.
8:35 SLiCEing Recombinant Antibody Expression Constructs
James Dasch, Ph.D., CSO, Abazyme LLC
Antibodies serve as a cornerstone of basic research, diagnostics and therapeutics. Using hybridomas as the starting material, our proprietary ACE process allows cloning of rodent heavy and light chains. Advances in ligation independent cloning methods such as In-fusion or cold fusion have helped facilitate cloning without the need for specialized vectors or for ligase. Using the recently described SLiCE technology, we find that SLiCE allows heavy chain, linker, and light chain insertion into any new vector in a single step without need for T4 polymerase, ligase or cleanup. SliCE portends a robust method for library construction. Abazyme is bringing the advances in antibody engineering, formerly used only for therapeutic antibodies, to the research marketplace.
8:50 Quantum Dot-Conjugated Antibodies as Diagnostic and Therapeutic Tools for Cancer Imaging and Treatment
Weiming Xu, Ph.D., CEO, London Biotech Ltd.
The conjugates of mAbs and nanoparticles, including quantum-dots (QDs), offer significant advantages over conventional fluorescent probes to image and study biological processes. The extended stability and low toxicity of QDs are well suited for biological applications. By conjugating QDs with small antibody fragments targeting membrane-bound proteins, such as GRP78, we demonstrated that the Quantum dot- Anti-GRP78 scFv (Qdot-GRP78) retains its immunespecificity and its distribution can be monitored by visualization of multi-color fluorescence imaging both in vitro and in vivo. Moreover we have shown for the first time that Qdot-GRP78 scFv bioconjugates can be efficiently internalized and possess biological anti-tumor activity in a breast cancer xenograft model. A recent pioneering study using primates for Qdots toxicity study has shown its nanocrystals to be safe over a one-year period, so the nanocarrier-conjugated antibody fragment has potential to become a new therapeutic tool for cancer treatment.
9:05 Native & Full Length Membrane Protein Isolation for Antibody Development and Drug Discovery. Solutions from The Membrane Protein Alliance
Anass Jawhari, Ph.D., CSO, CALIXAR SAS
CALIXAR and SYNTHELIS (two French Biotechs, Lyon and Grenoble) team up within the “Membrane Protein Alliance” to offer complete R&D services on native membrane protein isolation for drug discovery. CALIXAR offers a patented technological platform allowing to express, extract, purify and stabilize in solution full length membrane proteins (GPCRs, Ion Channels, Transporters, Receptors and Viral Proteins), while keeping their structural and functionality integrity (without refolding steps and avoiding mutagenesis). The native protein targets can be expressed in various systems such as cell free, E. coli, yeast, insect cells, CHO or HEK cells. Our approach can be used to generate conformational antibodies. SYNTHELIS’ proprietary technology enables the embedding of membrane proteins in liposomes directly during the translation step, allowing the production of active “ready-to-use”proteoliposomes for the antibody production.
9:20 The MPS™ Platform for Discovery of Antibodies against Difficult Membrane Protein Targets
Benjamin Doranz, Ph.D., President and CSO, Integral Molecular, Inc.
Integral’s MPS™ platform enables the isolation, characterization, and engineering of monoclonal antibodies (mAbs) for challenging but highly sought after membrane protein targets, including GPCRs and ion channels. MPS™ harnesses the strength of Integral’s 10+ years of expertise in membrane protein expression and analysis, as well as proprietary technologies including Lipoparticles for high concentration membrane protein presentation and Shotgun Mutagenesis for comprehensive epitope mapping and mAb optimization. Integral Molecular currently has a pipeline of several dozen mAbs against complex membrane proteins that are involved in a variety of diseases, including cancer, inflammation, pain, and infectious diseases. There are currently no FDA approved mAbs that target GPCRs, ion channels, or transporters, and MPS™ provides a pathway to previously intractable targets.
9:35 Networking Coffee Break
10:00 Building a Product Pipeline in the Cancer Immune Checkpoint Target Space in Capital Constrained Times
Robert Burns, Ph.D., CEO, 4-Antibody AG
4-Antibody’s Retrocyte Display antibody discovery platform is a powerful enabling technology. However, unlike a decade ago, there are now many highly effective and efficient antibody generation platforms available to corporate pharma - it’s now a buyer’s market. Like other companies in this space, 4-Antibody has been working hard to apply its technology platform to generate products which (it can be argued) have higher value in today’s technology replete market environment than platforms.
10:15 PENTRA®: A Tissue-Penetrating Class of Antibodies for Dermatology and Other Diseases
Titus Kretzschmar, CSO, Delenex Therapeutics AG
Three out of the 25 currently actively marketed monoclonal antibody drugs are small, so-called antibody fragments with combined sales of $3.6 billion in 2010. The other 22 molecules display molecular weights exceeding 100 kDa. Primarily because of their size, these large antibodies are administered either intravenously, or, more and more often, subcutaneously, eventually leading to systemic flooding of patients with such potent biologicals in indications where spatially and temporally restricted effects are preferred (“sledgehammer-approach”). With the advent of smaller, robust, high affinity antibody fragments, alternative delivery routes to confined body compartments with more favorable PK/PD parameters are amenable, leading to more efficacious drugs with fewer side effects and lower production costs (“tweezers-approach”).
10:30 Tanibirumab Phase I Study and GBM/HCC Phase II Preparation and its Rationale
Jin-San Yoo, Ph.D., President and CEO, PharmAbcine, Inc.
The only anti-KDR neutralizing fully human IgG1 antibody with cross-species cross reactivity, Tanibirumab phase I will be completed early next year and I will update the results and introduce our phase II plan for GBM and HCC. PharmAbcine is looking for partner who wants to develop Tanibirumab for US and European markets. It will be the first presentation with Phase I complete data.
10:45 Development of Angiogenesis Inhibitors Targeting Pathways Other than VEGF
Charles Theuer, Ph.D., CEO, TRACON Pharmaceuticals, Inc.
Monoclonal antibodies have revolutionized cancer care and four antibodies now have annual commercial revenues of greater than $1B annually. One of these antibodies, bevacizumab targets the VEGF pathway, which is essential for angiogenesis. Its success has prompted the development of a host of biologic therapies targeting this pathway. Efforts have now focused on targets that complement the VEGF pathway to further inhibit angiogenesis and positively impact cancer care. One example of a second generation angiogenesis target is CD105. The antibody TRC105 binds to CD105 (or endoglin), a target that (like VEGF) is required for angiogenesis, prognostically relevant and expressed within the vasculature of multiple solid tumors. Xenograft data indicates that targeting the CD105 pathway may be a useful strategy to combine with VEGF inhibition. The antibody is being studied in seven Phase 2 or Phase 1b trials in cancer patients.
11:00 Breakout Discussions with Morning Speakers and Lunch
12:45 pm Chairperson’s Remarks
12:50 PANEL DISCUSSION: Prospects for Protein Engineering and Novel Therapeutic Proteins
Luke Li, Ph.D., Executive Director, Bioinnovation, Pfizer, Inc.
Margaret Karow, Ph.D., Executive Director, Biologics, Amgen, Inc.
Kevin Johnson, Partner, Index Venture Manaagement LLP
Ray Camphausen, Associate Vice President Protein Design, Adnexus, a Bristol Myers Squibb R&D Co.
1:20 The Better Biologic: Algorithms, Repertoire Sequencing and Synthetic Library Design
Jacob Glanville, Scientific Director, Distributed Bio LLC
The combination of high-throughput sequencing and novel library synthesis methods is revolutionizing the way biologics are engineered. Affinity, stability, biochemical liability, cross-reactivity, half-life, immunogenicity: what once were disparate bioengineering considerations can now be combined and solved simultaneously using appropriate library design algorithms and selection methods. This presentation will provide practical demonstrations of how complex engineering goals can be integrated into synthetic antibody library designs. The talk will provide exposure on how to recover engineering principles from natural repertoires, how to optimize libraries with library design algorithms, and the practical considerations of how these approaches compare with traditional bioengineering practice.
1:35 ImmTACS: A Novel Class of Bispecifics for Cancer
Stephen Megit, Ph.D., Senior Business Development Manager, Immunocore Ltd.
ImmTACs are soluble, high affinity T cell Receptors fused to an anti-CD3 scFv domain for re-directed T cell killing of tumors. A key differentiating factor of this technology is the ability to target HLA presented epitopes, a previously unexplored class of antigen which includes many cancer specific targets. A melanoma specific ImmTAC, IMCgp100, is undergoing clinical testing in the UK and the US; it is well tolerated and induces T cell mobilization and tumor shrinkage. Immunocore has a pipeline of TCRs which target peptide antigens not accessible to therapeutic antibodies, since they are derived from intracellular proteins. The TCRs are fused to an anti-CD3 scFv which, much like Micromet’s BiTE technology (now validated in the clinic), activates a highly potent and specific anti-tumor response.
1:50 A Novel Strategy to Engineer Agonists and Antagonists to Complex Membrane Targets Utilizing V(D)J Recombination in a Mammalian Cell
Michael Gallo, President, Innovative Targeting Solutions, Inc.
Although antibodies have been generated against numerous epitopes, there are important clinically relevant receptor classes, including GPCRs and ion channels, which have historically been difficult to target. We report the use of a mammalian display system to graft peptides with reactivity to complex membrane antigens into the CDRs of the full length human IgG scaffold. Characterization of a library of greater than 100 million peptide variants generated in the context of all the human heavy chain variable and human light chain variable gene segments is presented. The advantages of diversifying both the length and composition of peptide flanking sequences as well as strategies to isolate rare variants with the desired properties are described.
2:05 Affimers: Engineered Alternatives to Antibodies that Provide a Toolkit for Discovery and Dissection of Biological and Pathological Processes
Paul Ko Ferrigno, Ph.D., Group Head, Discovery Technology, Avacta Group plc
Genomic and proteomic approaches produce overwhelming amounts of data, but do not allow rapid confirmation of even the most salient findings. Affimers are biophysically robust engineered alternatives to antibodies derived from a protease inhibitor, Stefin A, providing exceptional biological stability. They can be used for discovery (hypothesis generation) but also and uniquely for hypothesis validation too, from intracellular environments to in vitro biochemistry. Libraries of Affimers can be used for in vivo or in vitro screens, and the Affimer that identifies a biological event becomes the tool used to document and validate the underlying biology. This technology that can be used from discovery (high complexity Affimer Arrays) to validation (Affimers can be used to biochemically isolate their targets, as individual proteins or as protein complexes; they can be expressed inside cells to inhibit or promote protein activities), we now wish to make it as broadly available as possible. This will largely be through an Open Source format, where scientists in industry and academia are provided with the tools at no charge, providing that they make the data available via a freely accessible website.
2:20 A Novel Yeast Display for Discovering and Engineering IgG Antibodies and other Complex Proteins
Andy Rakestraw, Ph.D., Scientific Founder and Head, Technology, Celexion LLC
A novel form of yeast display has been used for IgG discovery and engineering as well as the engineering and evolution of other complex proteins. The novel system involves the in vivo biotinylation of a protein to be displayed, followed by secretion, and then capture by avidin bound to the surface of the parent cell. In this way proteins may be displayed without the need for cell wall fusion thus facilitating the display of complex, multi-peptide proteins such as IgG. In this presentation, we describe how to use this novel “secretion-and-capture” SECANT® display to perform antibody discovery from a proprietary, fully-human, naïve IgG antibody library. We also show how we were able to use the platform to engineer the display and binding of a non-IgG therapeutic protein. In this example, we take a complex biotherapeutic and, through careful strain and gene design, are able to create a powerful platform for engineering the therapeutic for higher target affinity.
2:35 Fynomab Platform for the Generation of Unique Bispecific Biotherapeutics
Fabian Buller, Ph.D., Director, Business Development, Covagen AG
Covagen is developing Fynomers and bispecific Fynomer-antibody fusions (FynomAbs) as next generation protein drugs to address unmet medical needs in inflammatory diseases and cancer. Fynomers are small binding proteins that can be engineered to bind to any antigen of interest. Because of their excellent biophysical properties, Fynomers can be readily fused to therapeutic proteins such as antibodies to create bispecific FynomAbs. FynomAbs have novel modes of action as they can engage simultaneously with multiple antigens or multiple binding sites on the same target. At the same time, FynomAbs maintain the advantageous drug-like properties of antibodies such as excellent stability and long half-life.
2:50 One molecule – Six Binding Sites: Second Generation TRAIL Receptor Agonists for the Treatment of Solid Tumors. Update 2013
Oliver Hill, Vice President, Molecular Biology, Apogenix GmbH
Apogenix has designed a new class of modular TRAIL-receptor agonists with lead candidates currently undergoing biopharmaceutical process development. The main feature of these protein therapeutics is a TRAIL mimic combining three TRAIL protomer subsequences in one polypeptide chain, termed single-chain-TRAIL-receptor-binding-domain (scTRAIL-RBD). The prototype of this engineering concept, APG350, distinguishes itself from current agonistic anti-TRAIL-R1 or TRAIL-R2 antibodies in clinical development by its ability to form defined TRAIL-receptor hexamers on target cells leading to rapid caspase-8 cleavage and subsequent apoptotic cell death of sensitive tumor cells in vivo. Due to their unique molecular layout, Apogenix’s proprietary scTRAIL-RBD protein therapeutics have the potential to bridge the gap between preclinical and clinical efficacy observed for current TRAIL-receptor agonists in oncology.
3:05 Development of Peptide and Peptidomimetic Therapeutics Using a Unique Disulfide-Rich Peptide Technology Platform
Dinesh Patel, Ph.D., President & CEO, Protagonist Therapeutics, Inc.
3:20 D-Proteins as a New Class of Human Therapeutics
Dana Ault-Riche, Ph.D., CEO, Reflexion Pharmaceuticals, Inc.
Small proteins (30 to 80 amino acids in size) have historically been under-utilized as therapeutic molecules because they are either rapidly metabolized or immunogenic. Making small proteins entirely out of D-amino acids, instead of the naturally occurring L-amino acids, overcomes both of these limitations. Reflexion is using small D-proteins to treat a variety of human diseases, including eye and lung diseases.
3:35 Breakout Discussions with Afternoon Speakers
4:15 PLENARY KEYNOTE PANEL
5:30 Close of Conference
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