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Beyond Antibodies Agenda
Beyond Antibodies
Main Conference: Monday | Main Conference: Tuesday | Main Conference: Wednesday
7:15
Registration and Coffee
8:00
Chairperson's Remarks
David S. Wilson, Ph.D., Vice President of Biologics Acquisitions and Validation, Cephalon, Inc.
David S. Wilson, Ph.D., Vice President of Biologics Acquisitions and Validation, Cephalon, Inc.
Keynote Presentation
8:10
Design, Evolution and Applications of Repeat ProteinsIn therapy, the creation of very robust proteins makes new applications possible. Progress in using Designed Ankyrin Repeat Proteins (DARPins) for this purpose will be discussed. In proteomics, the challenge will be to circumvent the tedious individual generation of binding proteins against every member of a proteome. Instead, modular approaches must be found. Progress on using Armadillo Repeat Proteins for this purpose will be discussed.
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zurich, Switzerland
Novel Scaffolds
8:40
Engineered Antibody VH and CH2 Domains as Potential Therapeutics
Engineered single antibody domains are small and can access targets and epitopes that are not accessible by larger molecules. We have constructed two large VH-based libraries of high diversity from which several high affinity domain antibodies against HIV and cancer-related proteins were identified and characterized with potential use as therapeutics. We have also engineered human antibody constant domains (CH2) as scaffolds which are highly stable, soluble, and express at high levels. Based on these new scaffolds, several libraries have been constructed, and binders were selected and characterized. Further engineering to confer additional functions (nanoantibodies) is in progress.
Dimiter Dimitrov, Ph.D., Senior Investigator, National Cancer Institute, NIH
Engineered single antibody domains are small and can access targets and epitopes that are not accessible by larger molecules. We have constructed two large VH-based libraries of high diversity from which several high affinity domain antibodies against HIV and cancer-related proteins were identified and characterized with potential use as therapeutics. We have also engineered human antibody constant domains (CH2) as scaffolds which are highly stable, soluble, and express at high levels. Based on these new scaffolds, several libraries have been constructed, and binders were selected and characterized. Further engineering to confer additional functions (nanoantibodies) is in progress.
Dimiter Dimitrov, Ph.D., Senior Investigator, National Cancer Institute, NIH
9:05
Mining Novel Scaffolds from Nature
The chemokine binding proteins identified in ticks have novel folds with no homologues in the pdb database. Understanding the binding modalities of these extremely small proteins which are smaller than the single chain camel antibodies or nanobodies, and have potent anti-inflammatory properties, will help us design better anti-inflammatory therapies.
Amanda Proudfoot, Ph.D., Principal Scientist, Autoimmmune and Inflammatory Diseases, Merck Serono Geneva Research Centre, Switzerland
The chemokine binding proteins identified in ticks have novel folds with no homologues in the pdb database. Understanding the binding modalities of these extremely small proteins which are smaller than the single chain camel antibodies or nanobodies, and have potent anti-inflammatory properties, will help us design better anti-inflammatory therapies.
Amanda Proudfoot, Ph.D., Principal Scientist, Autoimmmune and Inflammatory Diseases, Merck Serono Geneva Research Centre, Switzerland
9:30
Bicyclic Peptides with Tailored Binding Specificities
We are generating bicyclic peptide ligands with high affinities and specificities for disease targets using an approach recently developed with Sir Greg Winter at the Laboratory of Molecular Biology (LMB) in Cambridge, UK. Linear peptides on phage are chemically modified to obtain phage-encoded combinatorial libraries of bicyclic peptides, and binders are isolated in affinity selections. The bicyclic peptides combine key qualities of antibody therapeutics (high affinity and specificity) and advantages of small molecule drugs.
Christian Heinis, Ph.D., Assistant Professor, Ecole PolyTechnique Federale de Lausanne; Founder, Bicycle Therapeutics, Switzerland
We are generating bicyclic peptide ligands with high affinities and specificities for disease targets using an approach recently developed with Sir Greg Winter at the Laboratory of Molecular Biology (LMB) in Cambridge, UK. Linear peptides on phage are chemically modified to obtain phage-encoded combinatorial libraries of bicyclic peptides, and binders are isolated in affinity selections. The bicyclic peptides combine key qualities of antibody therapeutics (high affinity and specificity) and advantages of small molecule drugs.
Christian Heinis, Ph.D., Assistant Professor, Ecole PolyTechnique Federale de Lausanne; Founder, Bicycle Therapeutics, Switzerland
9:55
Q&A Panel Discussion with Morning Speakers
10:15
Networking Refreshment Break
10:45
Advances in DARPins and Centyrins: New Biotherapeutic Platforms for J&J
Alternative scaffold proteins combine many of the best properties of monoclonal antibodies and small molecules. In addition, their unique properties make them excellent candidates for novel delivery strategies and applications that require good tissue penetration. We are developing two complementary scaffolds to address targets and applications that are challenging by other proven strategies. New data will be presented demonstrating the advancement of DARPins and Centyrins into protein platforms tailored towards the therapeutic application.
Karyn O'Neil, Ph.D., Chief Scientific Officer, Johnson & Johnson Ventures, Centocor R&D
Alternative scaffold proteins combine many of the best properties of monoclonal antibodies and small molecules. In addition, their unique properties make them excellent candidates for novel delivery strategies and applications that require good tissue penetration. We are developing two complementary scaffolds to address targets and applications that are challenging by other proven strategies. New data will be presented demonstrating the advancement of DARPins and Centyrins into protein platforms tailored towards the therapeutic application.
Karyn O'Neil, Ph.D., Chief Scientific Officer, Johnson & Johnson Ventures, Centocor R&D
11:10
Fynomers Neutralizing Human IL-17A
We present data showing that many different functional Fynomer formats (dimers, trimers, bi-specifics and a variety of different Fc fusion proteins) can be assembled in a modular manner. In particular, we present the isolation and characterization of Fyn SH3 derived proteins binding to human IL-17A, a pro-inflammatory cytokine. Specific, high-affinity Fynomers show a remarkable ability to block IL-17A mediated effects in vitro and in vivo. Furthermore, engineered Fynomer-Fc fusion proteins have appropriate physico-chemical and in vivo half-life properties, making them attractive as drug candidates to be brought into pre-clinical and clinical development.
Dragan Grabulovski, Ph.D., Chief Scientific Officer, Covagen AG, Switzerland
We present data showing that many different functional Fynomer formats (dimers, trimers, bi-specifics and a variety of different Fc fusion proteins) can be assembled in a modular manner. In particular, we present the isolation and characterization of Fyn SH3 derived proteins binding to human IL-17A, a pro-inflammatory cytokine. Specific, high-affinity Fynomers show a remarkable ability to block IL-17A mediated effects in vitro and in vivo. Furthermore, engineered Fynomer-Fc fusion proteins have appropriate physico-chemical and in vivo half-life properties, making them attractive as drug candidates to be brought into pre-clinical and clinical development.
Dragan Grabulovski, Ph.D., Chief Scientific Officer, Covagen AG, Switzerland
11:35
Combining mAbs and dAbs: Generation of Dual-targeting Antibodies and Their Preclinical Development
Domain Antibodies (dAbs) are the smallest functional binding fragments of human antibodies. By combining different dAbs and mAbs as genetic fusions, we are creating a suite of novel bispecific agents that offer enhanced efficacy in a range of indications. We will show that these molecules will provide differentiated, developable biopharmaceuticals, and by virtue of their modular nature offer up a pipeline of further such molecules in the future.
Claire Ashman, Senior Scientific Investigator, Discovery Biology, GSK Biopharm R&D, GlaxoSmithKline Medicines Research Center, United Kingdom
Domain Antibodies (dAbs) are the smallest functional binding fragments of human antibodies. By combining different dAbs and mAbs as genetic fusions, we are creating a suite of novel bispecific agents that offer enhanced efficacy in a range of indications. We will show that these molecules will provide differentiated, developable biopharmaceuticals, and by virtue of their modular nature offer up a pipeline of further such molecules in the future.
Claire Ashman, Senior Scientific Investigator, Discovery Biology, GSK Biopharm R&D, GlaxoSmithKline Medicines Research Center, United Kingdom
12:00
Discovery and Optimization of a Nanobody-Based Therapeutic against IL6R
Nanobodies® are therapeutic proteins based on the smallest functional domain of heavy chain antibodies, which occur naturally in camels and llamas. Due to their intrinsic biophysical properties, Nanobodies can combine the advantages of small molecules and conventional monoclonal antibody therapeutics. This presentation will focus on the discovery and optimization of neutralizing Nanobodies against IL6 receptor. Highly potent and selective Nanobodies with predefined characteristics were generated and further optimized for therapeutic use.
Joost Kolkman, Ph.D., Associate Director Lead Optimization, Ablynx, Belgium
Nanobodies® are therapeutic proteins based on the smallest functional domain of heavy chain antibodies, which occur naturally in camels and llamas. Due to their intrinsic biophysical properties, Nanobodies can combine the advantages of small molecules and conventional monoclonal antibody therapeutics. This presentation will focus on the discovery and optimization of neutralizing Nanobodies against IL6 receptor. Highly potent and selective Nanobodies with predefined characteristics were generated and further optimized for therapeutic use.
Joost Kolkman, Ph.D., Associate Director Lead Optimization, Ablynx, Belgium
12:25
Q&A Panel Discussion with Morning Speakers
12:45
Lunch on your own
1:45
Chairperson's Remarks
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zurich, Switzerland
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zurich, Switzerland
Fusion Proteins and Conjugates
2:00
Fusion Proteins of Recombinant Antibodies with an Enzyme Effector
Pretargeted antibody-enzyme fusion proteins can provide an effective means to achieve selective cancer therapy by intra-tumor activation of a subsequently administered prodrug. The system can be used to generate a potent cytotoxic in the tumor mass; turning cancer deposits into factories for their own destruction. Feasibility and new developments with antibody-enzyme fusion proteins will be discussed using a bedside-to-bench approach.
Kerry Chester, Ph.D., Professor of Molecular Medicine and Group Leader, UCL Cancer Institute, United Kingdom
Pretargeted antibody-enzyme fusion proteins can provide an effective means to achieve selective cancer therapy by intra-tumor activation of a subsequently administered prodrug. The system can be used to generate a potent cytotoxic in the tumor mass; turning cancer deposits into factories for their own destruction. Feasibility and new developments with antibody-enzyme fusion proteins will be discussed using a bedside-to-bench approach.
Kerry Chester, Ph.D., Professor of Molecular Medicine and Group Leader, UCL Cancer Institute, United Kingdom
2:25
Phase I/II Clinical Trial Results of Tumor-targeting Antibody-cytokine Fusion Proteins of the Philogen Pipeline
Philogen focuses on the development of new biopharmaceuticals for the treatment of angiogenesis-related disorders. Angiogenesis is a characteristic feature of many severe pathologies such as cancer, rheumatoid arthritis and age-related macular degeneration. At present, Philogen has seven promising anti-cancer antibody derivatives and an antibody-derivative for the treatment of rheumatoid arthritis in Phase I/II clinical studies. The most recent results from these clinical trials will be presented.
Manuela Kaspar, Ph.D., Head of Protein Engineering, Philochem AG/Philogen S.p.A., Switzerland
Philogen focuses on the development of new biopharmaceuticals for the treatment of angiogenesis-related disorders. Angiogenesis is a characteristic feature of many severe pathologies such as cancer, rheumatoid arthritis and age-related macular degeneration. At present, Philogen has seven promising anti-cancer antibody derivatives and an antibody-derivative for the treatment of rheumatoid arthritis in Phase I/II clinical studies. The most recent results from these clinical trials will be presented.
Manuela Kaspar, Ph.D., Head of Protein Engineering, Philochem AG/Philogen S.p.A., Switzerland
2:50
Immunotoxins: A Rational Design Approach for the Treatment of Solid Cancers
Solid cancers present physiologic challenges for conventional antibody-based therapies that have resulted in only modest clinical benefit to date. We have engineered a variety of antibody-toxin fusion proteins to create a pipeline of highly potent anticancer agents for use against solid cancers. Our unique discovery approach, molecular design rationale, biological characterization and clinical experience with these molecules are presented.
Glen MacDonald, Ph.D., Chief Scientific Officer and VP, Operations, Viventia Biotechnologies, Inc.
Solid cancers present physiologic challenges for conventional antibody-based therapies that have resulted in only modest clinical benefit to date. We have engineered a variety of antibody-toxin fusion proteins to create a pipeline of highly potent anticancer agents for use against solid cancers. Our unique discovery approach, molecular design rationale, biological characterization and clinical experience with these molecules are presented.
Glen MacDonald, Ph.D., Chief Scientific Officer and VP, Operations, Viventia Biotechnologies, Inc.
3:15
Antibody-Drug Conjugates for Cancer Therapy
There are several aspects in ADC design that influence activity, safety, and specificity. Included among them are the antigen target, the drug/linker combination employed, and mode and multiplicity of drug/linker attachment to the mAb delivery vehicle. SGN-35 consists of the potent antimitotic agent monomethylauristatin E (MMAE), conjugated to an anti-CD30 mAb through a protease-sensitive linker. This presentation will relate the results of SGN-35, related ADCs, and will provide an overview of the challenges that lie ahead.
Dennis R. Benjamin, Ph.D., Senior Director, Chemistry and Antibody Technologies, Seattle Genetics
There are several aspects in ADC design that influence activity, safety, and specificity. Included among them are the antigen target, the drug/linker combination employed, and mode and multiplicity of drug/linker attachment to the mAb delivery vehicle. SGN-35 consists of the potent antimitotic agent monomethylauristatin E (MMAE), conjugated to an anti-CD30 mAb through a protease-sensitive linker. This presentation will relate the results of SGN-35, related ADCs, and will provide an overview of the challenges that lie ahead.
Dennis R. Benjamin, Ph.D., Senior Director, Chemistry and Antibody Technologies, Seattle Genetics
3:40
Q&A Panel Discussion with Afternoon Speakers
4:00
Networking Refreshment Break
Featured Presentation
4:30
Subvisible Aggregates and their Impact on Immunogenicity
It is well established that large protein aggregates are produced during the pharmaceutical manufacturing of therapeutic protein products and can enhance immunogenicity. In turn, the patients' immune response can compromise the efficacy and safety of the therapeutic protein. This talk will focus on 0.2-10 µm subvisible protein aggregates, how they may interact with the immune system, the potential impact these particles may have on a product's safety and efficacy profile, the factors affecting this risk, and recent efforts to evaluate and control the associated risk.
Jack Ragheb, M.D., Ph.D., Principal Investigator and Senior Regulatory Research Officer, Laboratory of Immunology, CDER, US FDA
It is well established that large protein aggregates are produced during the pharmaceutical manufacturing of therapeutic protein products and can enhance immunogenicity. In turn, the patients' immune response can compromise the efficacy and safety of the therapeutic protein. This talk will focus on 0.2-10 µm subvisible protein aggregates, how they may interact with the immune system, the potential impact these particles may have on a product's safety and efficacy profile, the factors affecting this risk, and recent efforts to evaluate and control the associated risk.
Jack Ragheb, M.D., Ph.D., Principal Investigator and Senior Regulatory Research Officer, Laboratory of Immunology, CDER, US FDA
Panel Discussion
5:00
Managing Immunogenicity of Therapeutic Proteins
Matthew Baker, Ph.D., Chief Scientific Officer, Antitope, United Kingdom
Jack Ragheb, M.D., Ph.D., Principal Investigator and Senior Regulatory Research Officer, Laboratory of Immunology, CDER, US FDA
- Regulatory expectations and lessons learned
- Development and validation of immunogenicity assays
- Predicting and engineering reduced immunogenicity
- Strategies for antibodies and alternative scaffolds
Matthew Baker, Ph.D., Chief Scientific Officer, Antitope, United Kingdom
Jack Ragheb, M.D., Ph.D., Principal Investigator and Senior Regulatory Research Officer, Laboratory of Immunology, CDER, US FDA
5:30
Close of Day One
Main Conference: Monday | Main Conference: Tuesday | Main Conference: Wednesday
7:45
Morning Coffee
8:00
Chairperson's Remarks
H. Kaspar Binz, Ph.D., Vice President Technology and Co-Founder, Molecular Partners, Switzerland
H. Kaspar Binz, Ph.D., Vice President Technology and Co-Founder, Molecular Partners, Switzerland
Engineering Bispecific and Multifunctional Proteins
Keynote Presentation
8:15
Antibody Combinations and Bispecific Antibodies Potently Neutralize Botulinum NeurotoxinsWe have generated human monoclonal antibodies that neutralize botulinum neurotoxins. When individual mAbs are combined, the potency of neutralization increases dramatically. Strategies to capture this potency in a single antibody based molecule will be described.
James D. Marks, M.D., Ph.D., Professor, Department of Anesthesia and Pharmaceutical Chemistry, Member, Comprehensive Cancer Center, University of California, San Francisco
8:45
mAb2: Novel Bispecific Antibodies that are Minimally Changed from IgG
We have developed two novel antibody formats: Fcab, in which antigen-binding sites are introduced into a human Fc fragment and mAb2, in which additional binding sites are engineered into the Fc of an intact antibody. Fcabs allow small therapeutic antibody fragments to be isolated that retain all normal antibody functionalities (antigen binding, effector functions and long half life) while mAb2 represents an elegant way to create bispecific antibodies.
Max Woisetschlager, Ph.D., Director of Target Biology, f-star, Austria
We have developed two novel antibody formats: Fcab, in which antigen-binding sites are introduced into a human Fc fragment and mAb2, in which additional binding sites are engineered into the Fc of an intact antibody. Fcabs allow small therapeutic antibody fragments to be isolated that retain all normal antibody functionalities (antigen binding, effector functions and long half life) while mAb2 represents an elegant way to create bispecific antibodies.
Max Woisetschlager, Ph.D., Director of Target Biology, f-star, Austria
9:10
Bispecific Antibodies: Delivering Combination Therapy in a Single Agent
Abstract not available at time of print.
Scott M. Glaser, Ph.D., Director, Antibody Therapeutics, Biogen Idec, Inc.
Abstract not available at time of print.
Scott M. Glaser, Ph.D., Director, Antibody Therapeutics, Biogen Idec, Inc.
9:35
Surrobodies with Functional Tails
Surrobodies™ are a unique type of antigen-binding protein based on the pre-B cell receptor (pre-BCR). Unlike canonical antibodies, the pre-BCR subunit is a trimer composed of an antibody heavy chain paired with a two subunit surrogate light chain (SLC). The heterodimeric surrogate light chain provides unique opportunities for protein engineering, namely the functional derivatization of their non-immunoglobulin-like tails. Through recent work with both of these novel tails we have recombinantly fused fully active cytokines to generate bifunctional Surrobodies, and similarly fused single chain Fv antibodies to form bispecific Surrobodies. Insights into the utility and combinatorial derivatization of this protein platform will be discussed.
Ramesh Bhatt, Ph.D., Vice President of Research, Sea Lane Biotechnologies
Surrobodies™ are a unique type of antigen-binding protein based on the pre-B cell receptor (pre-BCR). Unlike canonical antibodies, the pre-BCR subunit is a trimer composed of an antibody heavy chain paired with a two subunit surrogate light chain (SLC). The heterodimeric surrogate light chain provides unique opportunities for protein engineering, namely the functional derivatization of their non-immunoglobulin-like tails. Through recent work with both of these novel tails we have recombinantly fused fully active cytokines to generate bifunctional Surrobodies, and similarly fused single chain Fv antibodies to form bispecific Surrobodies. Insights into the utility and combinatorial derivatization of this protein platform will be discussed.
Ramesh Bhatt, Ph.D., Vice President of Research, Sea Lane Biotechnologies
10:00
Networking Refreshment Break and Poster/Exhibit Viewing
Keynote Presentation
10:30
Chemically Programmed Immunity: Antibodies and VaccinesRecently, we invented a new class of immunotherapeutics, Chemically Programmed Antibodies or CovX-bodies, now advancing in numerous clinical trials. This presentation will focus on fundamentals of cpAb technology, its applications, and its ongoing elaboration. Advancing this approach to vaccinology, we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology in cancer and infectious disease.
Carlos F. Barbas III, Ph.D., Kellogg Professor and Chair, The Skaggs Institute for Chemical Biology and the Departments of Molecular Biology and Chemistry, The Scripps Research Institute
Emerging Preclinical and Clinical Results
11:00
Advancing DARPins to the Clinic
DARPins are a high-affinity, low-immunogenicity-potential protein drugs that combine the advantages of antibodies and small molecule drugs. The favorable properties of DARPins enable the fast generation of a variety of drug candidates for different indications. MP0112, a best-in-class therapeutic program for the treatment of ocular neovascularization diseases will be presented along with other examples for therapeutic applications where DARPins are superior to monoclonal antibodies.
H. Kaspar Binz, Ph.D., Vice President, Technology and Co-Founder, Molecular Partners, Switzerland
DARPins are a high-affinity, low-immunogenicity-potential protein drugs that combine the advantages of antibodies and small molecule drugs. The favorable properties of DARPins enable the fast generation of a variety of drug candidates for different indications. MP0112, a best-in-class therapeutic program for the treatment of ocular neovascularization diseases will be presented along with other examples for therapeutic applications where DARPins are superior to monoclonal antibodies.
H. Kaspar Binz, Ph.D., Vice President, Technology and Co-Founder, Molecular Partners, Switzerland
11:25
Anticalins, A Unique Class of Targeted Protein Therapeutics
Anticalins are modified versions of human lipocalins. Pieris' lead project PRS-050 (VEGF antagonist) is now entering human studies. Unique features of this drug class such as the ability to bind therapeutically relevant hapten targets will be presented, along with their broad formulation and formatting flexibility.
Kristian Jensen, Ph.D., Chief Operating Officer, Pieris AG, Germany
Anticalins are modified versions of human lipocalins. Pieris' lead project PRS-050 (VEGF antagonist) is now entering human studies. Unique features of this drug class such as the ability to bind therapeutically relevant hapten targets will be presented, along with their broad formulation and formatting flexibility.
Kristian Jensen, Ph.D., Chief Operating Officer, Pieris AG, Germany
Featured Presentation
11:50
Monoclonal Antibodies, Next Generation Antibodies, and Antibody Alternatives: An FDA Perspective
The clinical success of therapeutic monoclonal antibodies in the 1990's spurred an increase in the number of these products in the development pipeline. Currently there are over 200 monoclonal antibodies in clinical development including 2nd generation products and novel antibody constructs. The FDA perspective on the regulation of these products, including quality considerations for different routes of administration and how to communicate with the appropriate review divisions will be discussed.
Ruth Cordoba-Rodriguez, Ph.D., Product Quality Reviewer, Division of Monoclonal Antibodies, Office of Biotechnology Products, CDER, US FDA
The clinical success of therapeutic monoclonal antibodies in the 1990's spurred an increase in the number of these products in the development pipeline. Currently there are over 200 monoclonal antibodies in clinical development including 2nd generation products and novel antibody constructs. The FDA perspective on the regulation of these products, including quality considerations for different routes of administration and how to communicate with the appropriate review divisions will be discussed.
Ruth Cordoba-Rodriguez, Ph.D., Product Quality Reviewer, Division of Monoclonal Antibodies, Office of Biotechnology Products, CDER, US FDA
12:10
Luncheon Discussion & Debate Sessions
(Lunch will be provided)
(Lunch will be provided)
-
Novel scaffolds and scaffold engineering
Discussion Leader: Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zurich, Switzerland -
Selection and library design
Discussion Leader: Jonathan Davis, Ph.D., Principal Scientist, Protein Design, Adnexus, a Bristol-Myers Squibb Company -
Strategies for plasma half-life extension of biopharmaceuticals
Discussion Leader: Arne Skerra, Ph.D., CEO, XL-protein GmbH, Germany -
De-immunization strategies
Discussion Leader: TBA -
What are the differentiators of next generation biologics in the marketplace?
Discussion Leader: Kristian Jensen, Ph.D., Chief Operating Officer, Pieris AG, Germany -
Blocking multimeric targets with bivalent IgGs; Does immune complex formation pose a safety risk?
Discussion Leader: Volker Schellenberger, Ph.D., Vice President, Drug Discovery, Amunix, Inc. -
Regulatory issues associated with next generation protein therapeutics
Discussion Leaders:
Jack Ragheb, M.D., Ph.D., Principal Investigator and Senior Regulatory Research Officer, Laboratory of Immunology, CDER, US FDA Ruth Cordoba-Rodriguez, Ph.D., Product Quality Reviewer, Division of Monoclonal Antibodies, Office of Biotechnology Products, CDER, US FDA -
Modulating the intracellular undruggable target space
Discussion Leader: Hanjo Hennemann, Ph.D., Executive Director and Head of R&D, Nexigen GmbH, Germany
1:15
Dessert and Exhibit/Poster Viewing
1:45
Chairperson's Remarks
Matthew Baker, Ph.D., Chief Scientific Officer, Antitope, United Kingdom
Matthew Baker, Ph.D., Chief Scientific Officer, Antitope, United Kingdom
Featured Presentation
2:00
Analysis and Prediction of HLA Class II Restricted Responses
Our group has been involved in the measurement of helper CD4 T cell reactivity in human populations, restricted by HLA class II, in a variety of experimental systems. In some instances responses are beneficial, like in the case of reactivities observed following vaccination or involved in resolution of microbial infections. In other instances the reactivity is undesired, like in the case of drug reactions and allergies. From these analyses overall, certain general features associated with helper CD4 responses in humans can be discerned. This information is relevant in the context of the different methodologies available to predict T cell reactivity, and potential modification to increase or reduce immunogenicity.
Alessandro Sette, Ph.D., Head and Member, Center for Infectious Diseases, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology
Our group has been involved in the measurement of helper CD4 T cell reactivity in human populations, restricted by HLA class II, in a variety of experimental systems. In some instances responses are beneficial, like in the case of reactivities observed following vaccination or involved in resolution of microbial infections. In other instances the reactivity is undesired, like in the case of drug reactions and allergies. From these analyses overall, certain general features associated with helper CD4 responses in humans can be discerned. This information is relevant in the context of the different methodologies available to predict T cell reactivity, and potential modification to increase or reduce immunogenicity.
Alessandro Sette, Ph.D., Head and Member, Center for Infectious Diseases, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology
Protein Design and Engineering to Minimize Immunogenicity
2:30
Deimmunization Strategy for Adnectins, Human Fibronectin Based Targeted Biologics
Immunogenicity assessment with in silico tools and in vitro T cell based assays opens the possibility to change the human immune response to therapeutic proteins by protein engineering. Here we will discuss the strategy for minimizing the immunogenic potential of Adnectins in the discovery stage.
Nick Marsh, Ph.D., Director of Pharmacology, Adnexus, a Bristol-Myers Squibb R&D Company
Immunogenicity assessment with in silico tools and in vitro T cell based assays opens the possibility to change the human immune response to therapeutic proteins by protein engineering. Here we will discuss the strategy for minimizing the immunogenic potential of Adnectins in the discovery stage.
Nick Marsh, Ph.D., Director of Pharmacology, Adnexus, a Bristol-Myers Squibb R&D Company
3:00
Deimmunizing Humanized and Fully Human Antibodies
We studied human CD4+ T cell responses in antibody V regions. Early attempts to deimmunize adalimumab were unsuccessful, demonstrating the limits of current methods. We selected functional, deimmunized variants only after the development and application of a comprehensive mutational analysis tool. Deimmunization of antibodies in general will be discussed.
Fiona A. Harding, Ph.D., Associate Director, New Technologies, Facet Biotech
We studied human CD4+ T cell responses in antibody V regions. Early attempts to deimmunize adalimumab were unsuccessful, demonstrating the limits of current methods. We selected functional, deimmunized variants only after the development and application of a comprehensive mutational analysis tool. Deimmunization of antibodies in general will be discussed.
Fiona A. Harding, Ph.D., Associate Director, New Technologies, Facet Biotech
3:30
Networking Refreshment Break and Exhibit/Poster Viewing
4:00
Activation of Natural Regulatory T cells by IgG Fc-derived Peptide "Tregitopes"
We have confirmed that co-administration of T regulatory epitopes (Tregitopes) with a range of proteins in vitro and in vivo leads to suppression of T cell and antibody responses to the test antigens. We have also demonstrated that Tregitopes are not immunogenic in vivo even emulsified with IFA or CFA. In this presentation, we will review the evidence that consideration of regulatory T cell induction represents a new paradigm for the suppression of immune response to protein therapeutics (like Factor VIII and novel scaffolds), as well as for treatment of autoimmune diseases.
Anne S. De Groot, M.D., Adjunct Associate Professor of Medicine, Brown University; Founder, CEO and CSO, EpiVax, Inc.
We have confirmed that co-administration of T regulatory epitopes (Tregitopes) with a range of proteins in vitro and in vivo leads to suppression of T cell and antibody responses to the test antigens. We have also demonstrated that Tregitopes are not immunogenic in vivo even emulsified with IFA or CFA. In this presentation, we will review the evidence that consideration of regulatory T cell induction represents a new paradigm for the suppression of immune response to protein therapeutics (like Factor VIII and novel scaffolds), as well as for treatment of autoimmune diseases.
Anne S. De Groot, M.D., Adjunct Associate Professor of Medicine, Brown University; Founder, CEO and CSO, EpiVax, Inc.
Immunogenicity and Alternative Scaffolds
4:30
Assessment of Clinical Immunogenicity for an Adnectin, a Novel Targeted Biologic Evaluated from a PK and PD Perspective
Adnectins are a novel, proprietary class of targeted biologics that are derived from human fibronectin, which is a well-characterized, highly-expressed plasma protein. This presentation will demonstrate the low risk immunogenicity profile of Adnectins, based on the minimal clinical relevance of the immune response in patients treated with CT-322, a VEGFR-2 inhibiting Adnectin.
Jochem Gokemeijer, Principal Scientist, Pharmacology, Adnexus, a Bristol-Myers Squibb R&D Company
Adnectins are a novel, proprietary class of targeted biologics that are derived from human fibronectin, which is a well-characterized, highly-expressed plasma protein. This presentation will demonstrate the low risk immunogenicity profile of Adnectins, based on the minimal clinical relevance of the immune response in patients treated with CT-322, a VEGFR-2 inhibiting Adnectin.
Jochem Gokemeijer, Principal Scientist, Pharmacology, Adnexus, a Bristol-Myers Squibb R&D Company
5:00
Monitoring Potential Immunogenicity: Experience with the First Nanobody® in Clinical Development
Currently 4 llama-derived Nanobodies are in clinical development. The first was the Ablynx anti-vWF Nanobody (ALX-0081). In Phase 1 trials completed to date over 80 subjects/patients have been exposed to ALX-0081 with no immunogenicity detected. Data will be presented on assessment of immunogenic potential of ALX-0081 from bench to bedside.
Debbie Law, Ph.D., Chief Scientific Officer, Ablynx, Belgium
Currently 4 llama-derived Nanobodies are in clinical development. The first was the Ablynx anti-vWF Nanobody (ALX-0081). In Phase 1 trials completed to date over 80 subjects/patients have been exposed to ALX-0081 with no immunogenicity detected. Data will be presented on assessment of immunogenic potential of ALX-0081 from bench to bedside.
Debbie Law, Ph.D., Chief Scientific Officer, Ablynx, Belgium
5:30
Close of Day Two
Main Conference: Monday | Main Conference: Tuesday | Main Conference: Wednesday
8:00
Morning Coffee
8:15
Chairperson's Remarks
Mark S. Dennis, Senior Scientist, Antibody Engineering, Genentech, Inc.
Mark S. Dennis, Senior Scientist, Antibody Engineering, Genentech, Inc.
Delivery of Alternative Scaffolds
8:45
Alternative Delivery of Nanobodies®
Llama-derived Nanobodies have inherent biophysical properties, including thermodynamic stability, resistance to pH and protease degradation, which make them ideal candidates for alternative methods of drug delivery. Data will be presented demonstrating that Nanobodies can be delivered via routes other than intravenous injection and retain their function when delivered via skin (SC), oral and pulmonary routes.
Hilde Revets, Ph.D., Senior Director, Technology, Ablynx, Belgium
Llama-derived Nanobodies have inherent biophysical properties, including thermodynamic stability, resistance to pH and protease degradation, which make them ideal candidates for alternative methods of drug delivery. Data will be presented demonstrating that Nanobodies can be delivered via routes other than intravenous injection and retain their function when delivered via skin (SC), oral and pulmonary routes.
Hilde Revets, Ph.D., Senior Director, Technology, Ablynx, Belgium
9:15
Pulmonary Delivered Domain Antibodies: anti-TNFR1 dAb for Lung Diseases
Due to their small size and stability, human domain antibodies (dAbs) can readily be delivered to the respiratory tract. We have demonstrated superior efficacy using low doses of pulmonary delivered dAb against the TNF receptor 1 in mouse models for COPD and acute inflammatory models in non-human primates. This data demonstrates utility of dAbs for pulmonary delivery and highlights the potential of TNFR1 as a target for treatment of pulmonary inflammatory diseases.
Peter J. Morley, Ph.D., Investigator, Discovery, Biopharm R&D, GlaxoSmithkline, United Kingdom
Due to their small size and stability, human domain antibodies (dAbs) can readily be delivered to the respiratory tract. We have demonstrated superior efficacy using low doses of pulmonary delivered dAb against the TNF receptor 1 in mouse models for COPD and acute inflammatory models in non-human primates. This data demonstrates utility of dAbs for pulmonary delivery and highlights the potential of TNFR1 as a target for treatment of pulmonary inflammatory diseases.
Peter J. Morley, Ph.D., Investigator, Discovery, Biopharm R&D, GlaxoSmithkline, United Kingdom
Crossing the Blood-Brain-Barrier
9:45
Delivering Antibodies across the BBB
The vascular and nervous systems form a tight interface in the central nervous system, known as the blood-brain barrier (BBB) that directs the flow of various molecules, including antibodies. We have designed experiments to better understand how the BBB forms and functions, with a particular focus on antibody dynamics at the BBB. This presentation will focus on our efforts to engineer antibodies targeting specific brain endothelial targets to enable receptor-mediated transport as a means to deliver antibodies across the BBB.
Mark S. Dennis, Senior Scientist, Antibody Engineering, Genentech, Inc.
The vascular and nervous systems form a tight interface in the central nervous system, known as the blood-brain barrier (BBB) that directs the flow of various molecules, including antibodies. We have designed experiments to better understand how the BBB forms and functions, with a particular focus on antibody dynamics at the BBB. This presentation will focus on our efforts to engineer antibodies targeting specific brain endothelial targets to enable receptor-mediated transport as a means to deliver antibodies across the BBB.
Mark S. Dennis, Senior Scientist, Antibody Engineering, Genentech, Inc.
10:15
Networking Refreshment Break and Exhibit/Poster Viewing
10:45
Re-Engineering Recombinant Proteins for the Brain with Blood-Brain Barrier Molecular Trojan Horse Technology
Recombinant proteins and monoclonal antibody therapeutics cannot be developed as drugs for the brain, because these large molecules do not cross the blood-brain barrier (BBB). To solve the BBB problem, recombinant proteins are re-engineered as IgG fusion proteins. The IgG is a peptidomimetic monoclonal antibody against the human BBB insulin receptor. The IgG acts as a molecular Trojan horse to ferry the protein pharmaceutical across the BBB via receptor-mediated transport.
William Pardridge, M.D., Chief Scientific Officer, ArmaGen Technologies, Inc.
Recombinant proteins and monoclonal antibody therapeutics cannot be developed as drugs for the brain, because these large molecules do not cross the blood-brain barrier (BBB). To solve the BBB problem, recombinant proteins are re-engineered as IgG fusion proteins. The IgG is a peptidomimetic monoclonal antibody against the human BBB insulin receptor. The IgG acts as a molecular Trojan horse to ferry the protein pharmaceutical across the BBB via receptor-mediated transport.
William Pardridge, M.D., Chief Scientific Officer, ArmaGen Technologies, Inc.
11:15
Screening Phylomer Libraries to Find the Ideal Structures for Particular Targets Inside or Outside Cells
Phylomer peptides can exhibit superior functional hit-rates, when compared to randomly derived peptides, due to evolutionary selection for structure and stability. We have exploited the high functional hit rates from Phylomer libraries, to allow direct screening for particular phenotypes and to identify multiple intracellular targets in vivo. Phylomer libraries can also be used to identify new protein transduction domains for delivery of macromolecules into cells. We will also present ex vivo and in vivo studies of potent blockers of the extracellular target CD40Ligand (CD40L) for inflammatory diseases, including the results of intranasal administration approaches.
Paul Watt, Ph.D., Chief Scientific Officer and VP, Corporate Development, Phylogica Ltd, Australia
Phylomer peptides can exhibit superior functional hit-rates, when compared to randomly derived peptides, due to evolutionary selection for structure and stability. We have exploited the high functional hit rates from Phylomer libraries, to allow direct screening for particular phenotypes and to identify multiple intracellular targets in vivo. Phylomer libraries can also be used to identify new protein transduction domains for delivery of macromolecules into cells. We will also present ex vivo and in vivo studies of potent blockers of the extracellular target CD40Ligand (CD40L) for inflammatory diseases, including the results of intranasal administration approaches.
Paul Watt, Ph.D., Chief Scientific Officer and VP, Corporate Development, Phylogica Ltd, Australia
11:45
Case Study for Intranasal Delivery of a Neuroprotective Peptide
Neuropeptide drug development requires an understanding of the mechanism and kinetics by which peptide gets into the central nervous system, including selection of the route of administration based on pharmacokinetics and pharmacodynamics. Davunetide is a neuroprotective peptide with broad-spectrum preclinical efficacy, currently in clinical development for dementia and cognitive impairment. Examples from the davunetide development program will be used to illustrate how these challenges can be addressed.
Bruce Morimoto, Ph.D., Vice President, Drug Development, Allon Therapeutics, Inc.
Neuropeptide drug development requires an understanding of the mechanism and kinetics by which peptide gets into the central nervous system, including selection of the route of administration based on pharmacokinetics and pharmacodynamics. Davunetide is a neuroprotective peptide with broad-spectrum preclinical efficacy, currently in clinical development for dementia and cognitive impairment. Examples from the davunetide development program will be used to illustrate how these challenges can be addressed.
Bruce Morimoto, Ph.D., Vice President, Drug Development, Allon Therapeutics, Inc.
12:15
Networking Luncheon and Exhibit/Poster Viewing
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