Cambridge Healthtech Institute’s 4th Annual

Optimization and Development of Biologics
Target Discovery, Enhanced Product Properties and Manufacturability, and Therapeutic Application
3-4 November 2014


Speaker BiographiesDownload Brochure | Register 

This track focuses on refinement of biotherapeutics for use in preclinical tox studies and further down the line in clinical development and ultimately for the marketed product. Research with industry experts reveals a huge concern for controlling half-life and stability, and for avoidance of aggregation and immunogenicity. Moreover, the wide range of therapeutic areas being addressed calls for unique delivery approaches. Manufacturability with good yields of potent and consistent batches is another important goal. This track will include all of these topics as well as reports from the pioneers in preclinical and clinical development.

Recommended Short Courses*

SC1: Engineering of Bispecific Antibodies

SC2: Mutation and Selection Strategies for Multi-Parameter Antibody Optimisation

SC6: Troubleshooting and Engineering of Antibody Constructs

(*Separate Registration Required.

Monday, 3 November

12:00 Conference Registration


PLENARY SESSION 

13:45 PEGS Europe Team Welcome 

13:50 Chairperson’s Opening Remarks 

William Finlay, Ph.D., Director, Global Biotherapeutic Technologies, Pfizer, Inc. 

14:00 The Impact of the New Regulatory Guidance Landscape on the Validation of the Manufacturing Process and the Characterisation of Starting Materials, Drug Substance and Drug Product 

Steffen GrossSteffen Gross, Ph.D., Head, Monoclonal and Polyclonal Antibodies, Paul-Ehrlich-Institut 

The regulatory guidance landscape regarding biological products changes rapidly. Documents overseeing process validation is currently facing major overhauls. New guidelines are published defining the requirements for starting materials and excipients. This might have a deep impact not only on the process development of traditional monoclonal antibody type products but also on new antibody formats such as conjugates as well as on new developed formulations. 

14:45 Current Progress with Armed Antibody Products 

Dario NeriDario Neri, Ph.D., Professor, Chemistry and Applied Biosciences, ETH Zurich 

There is an emerging trend in Pharmaceutical Biotechnology to “arm” antibodies, capable of selective localization at the site of disease, with suitable therapeutic payloads (e.g., drugs, cytokines, radionuclides, a second antibody moiety, hence producing a bispecific product). This strategy aims at concentrating therapeutic agents in diseased part of the body, while sparing normal tissues. In this lecture, I will present a comparative evaluation of different classes of armed antibody products, developed in my laboratory in collaboration with Philogen. In particular, I will present preclinical and clinical data of armed antibodies in the field of cancer, of chronic inflammation and of endometriosis. 


15:30 Refreshment Break


OPTIMISATION OF POTENCY, BINDING, STABILITY, AND RESISTANCE TO AGGREGATION

16:00 Chairperson’s Opening Remarks

WIlliamFinlayWilliam Finlay, Ph.D., Director, Global Biotherapeutic Technologies, Pfizer, Inc.





16:05 Differential Co-Engagement of TLR4 and FcγRs Modulates the Potency of NI-0101

JeremyLoyauJeremy Loyau, Scientist, Antibody Engineering Unit, Research, Novimmune SA

NI-0101 is a monoclonal antibody directed against TLR4 with a neutralizing mechanism enhanced by FcγR interactions. The antagonistic activity of NI-0101 can be modified based on valency, i.e., the level of co-engagement with different receptor types at the cell surface. The hierarchy for increased avidity is: TLR4 alone < TLR4 + FcγRII < TLR4+ FcγRI. This mode of action could be exploited in order to more efficiently or selectively neutralize other cell surface targets on cells expressing FcγRs.

16:35 Development and Application of TwoB-Ig: A Novel Engineered Fc Variant with Selectively- Enhanced Binding to FcγRIIb

HitoshiKatadaHitoshi Katada, Ph.D., Research Scientist, Discovery Research, Chugai Pharmaceutical Co. Ltd.

We have developed a novel engineered Fc platform named TwoB-Ig which has complete selectivity to FcγRIIb, an only inhibitory FcγR, over activating FcγR including both allotypes of FcγRIIa. This unique selectivity is important to exploit FcγRIIb for various applications. In vitro and in vivo data for the application of TwoB-Ig technology to improve pH-dependent antigen binding antibody and enhance agonistic activity of anti-TNFR antibody will be presented.

17:05 Dual-Affinity Re-Targeting DART Proteins for Oncology

SydJohnsonSyd Johnson, Ph.D., Vice President, Antibody Engineering, MacroGenics, Inc.

Bispecific antibodies that recruit effector cells to tumours represent a highly potent class of immunotherapeutic agents that may outperform or complement traditional chemotherapy, naked antibodies and ADCs. MacroGenics’ Dual-Affinity Re-Targeting (DART) proteins are among the most stable and potent biologics in this therapeutic class. An update will be presented on several DART candidates in different stages of development for treatment of hematological or solid tumours. Applications of half-life extended and non-extended DARTs will be discussed, as well as methods for their production.

Schrodinger logo17:35 Recent Advances and Successes in Computational Antibody Modeling Using BioLuminate
Pearlman_DavidDavid A. Pearlman, Ph.D., Senior Principal Scientist, Schrödinger 

We describe recent studies demonstrating the power of theoretical structure-based protein design tools as applied to antibodies, as well as our performance in a recent multi-institution blinded antibody structure prediction assessment, and demonstrate how computational tools can be used to perform analyses such as hot spot identification.

17:50 Sponsored Presentation (Opportunity Available)

18:05 Welcome Reception in the Exhibit Hall with Poster Viewing

19:05 End of Day One




Tuesday, 4 November

07:30 Registration

07:45 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee


OPTIMISATION OF MANUFACTURABILITY, RESISTANCE TO AGGREGATION AND SOLUBILITY

08:30 Chairperson’s Remarks

KasparBinzH. Kaspar Binz, Ph.D., Vice President & Co-Founder, Molecular Partners AG





08:40 Engineering Aggregation-Resistant Antibody Fragments

PeterTessierPeter Tessier, Ph.D., Associate Professor, Chemical & Biological Engineering, Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute

We are investigating how antibody fragments can be engineered to possess extremely high solubility without altering binding activity. We have developed a novel approach for engineering the edges of hydrophobic CDRs with charged insertion mutations that dramatically increases antibody solubility without reducing binding affinity. Our studies reveal that the location of charged mutations within CDRs as well as the polarity of such mutations dramatically impact their solubilizing activity.

09:10 Engineering, Purification and Optimisation of Bispecific Heavy Chain Heterodimers for T Cell Redirection

StanislasBleinStanislas Blein, Ph.D., Deputy Director & Head, Antibody Engineering, Biologics, Glenmark Pharmaceuticals

By combining FAB and scFv formats with a unique concept of bio-mimicry, we have developed a heavy chain heterodimerization platform wherein antibodies from different sources can be paired without any restrictions and subsequently manufactured. Bottlenecks such as achieving high levels of heterodimerization, removal of homodimer traces during scale-up, or scFv instability and aggregation have been solved to create an efficient and scalable process

09:40 Antibody v-Domain Optimisation for Subcutaneous Dosing Strategies

WIlliamFinlayWilliam Finlay, Ph.D., Director, Global Biotherapeutic Technologies, Pfizer, Inc.

While myriad molecular formats for bispecific antibodies have been examined, the simplest structures are often based on the scFv. Issues with stability and manufacturability in scFv-based bispecific molecules, however, have been a significant hindrance to their development, particularly for high-concentration, stable formulations that allow subcutaneous delivery. Using a novel CDR-based engineering strategy, we have generated a tetravalent bispecific molecule for subcutaneous administration. New insights into structure-function relationships will be presented.

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


DATA MANAGEMENT FOR ANTIBODY DISCOVERY

10:50 GSK’s Antibody Discovery Database (ADD), a Comprehensive System to Manage, Share and Exploit Antibody Discovery Processes and Format Information

TrevorWattam Trevor Wattam, Ph.D., Manager, Biopharm Discovery Group, GlaxoSmithKline

I will present an overview of a comprehensive R&D data management system referred to as the GSK’s Antibody Discovery Database (ADD), a comprehensive system used to manage, share and exploit the large amount of relevant and complex information from all our Antibody discovery processes (yeast display, phage display, hybridoma/humanization) and GSKs biopharm formats, including domain antibodies (dAbs), mAbs and bispecifics.

11:20 Veltis® Innovative Technology for Half-Life
Extension and Optimisation of Biotherapeutics

Atunes_FilipaFilipa Antunes, Msc, Ph.D., Research Scientist, Novozymes A/S

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. It has been demonstrated that the pharmacokinetics of small drugs, peptides and proteins can be significantly improved by conjugation, association or fusion to albumin. This extended circulatory half-life derives from both the size of albumin and recycling of the molecule via the neonatal Fc receptor, FcRn. Using advanced protein engineering expertise, human serum albumin has been modified to enhance its affinity for FcRn. This increase in affinity for the FcRn receptor translates into improved pharmacokinetic properties of the albumin molecule and ultimately the therapeutic candidate that is fused or conjugated to it. The application of these novel albumin variants to improve the pharmacokinetic properties of a number of therapeutic candidates, including proteins and small peptides will be presented and discussed.

 

 

 

 

 

 

11:50 Problem Solving Roundtable Discussions

Optimisation of Manufacturability

StanislasBleinModerator: Stanislas Blein, Ph.D., Deputy Director & Head, Antibody Engineering, Biologics, Glenmark Pharmaceuticals

  • Challenges of purifying novel formats compared with monoclonal antibodies
  • Ensuring that technologies work well for small and large scale manufacture
  • Designing a platform process transferable to CMOs
  • Experiences with physicochemical characterization and comparability
  • Practical issues such as cell lines, manufacturability, animal models
  • Experiences with manufacturability and quality issues

Measures to Avoid Off-Target Toxicity

Klaus BossletModerator: Klaus Bosslet, Ph.D., Head, Discovery Oncology, Roche Pharmaceuticals, Penzberg

  • Sharing of experiences
  • Options available for overcoming this difficulty


Engineering of Bispecific Antibodies

TonLogtenbergModerator: Ton Logtenberg, Ph.D., CEO, Merus

  • Criteria for selecting antibodies to generate bispecifics
  • screening for bi-specific targets with the desired functionality
  • Novel strategies for combining antibody moieties
  • Validation of the product in terms of having advantages over two separate antibodies
  • Design of molecule for ease of manufacture

Measures for Getting Biologically Active Antibodies

Moderator: Yanay Ofran, Ph.D., Founder, Biolojic Design, Ltd.;
Goodman Faculty of Life Sciences, BarIlan University

  • Can we select for activity, not only binding
  • Approaches for Rational Design of Antibodies
  • Targeting specific epitopes
  • Computational challenges for rational design of antibodies
  • Experimental challenges for rational design of antibodies
 

 Avacta logo12:50 Luncheon Presentation

Speaker to be Announced

14:00 Dessert Break in the Exhibit Hall with Poster Viewing


PRECISION ONCOLOGY, EPITOPE-SPECIFIC ANTIBODIES, AND MANAGEMENT OF TOXICITY

14:30 Chairperson’s Remarks

JulianBertschingerJulian Bertschinger, Ph.D., CEO, Covagen






KEYNOTE PRESENTATION

14:35 Next-Generation Cancer Treatment Using Multi-Specific Darpins

H Kaspar BinzH. Kaspar Binz, Ph.D., Vice President & Co-Founder, Molecular Partners AG

Precision oncology is an emerging treatment paradigm by which well-chosen targeted therapeutics will inhibit the specific tumour drivers of each patient. Such an approach will require the combination of several targeted therapeutics, which may be hampered by overlapping off-target toxicities and economic reasons, or ideally the availability of multi-specific therapeutics - a natural setting for DARPins given their high specificity and modular architecture. We have generated multi-specific DARPin drug candidates against various tumour drivers, which compare favorably in preclinical models to available standards of care. Insights on the rationale for target choice, drug format, mechanism of action and differentiation will be provided.


15:05 Computer-Guided Design and Validation of Epitope-Specific Antibodies against GPCRs and Ion-Channels

Yanay Ofran, Ph.D., Founder, Biolojic Design, Ltd.; Goodman Faculty of Life Sciences, BarIlan University

A major challenge in antibody discovery today is the development of biologically active Abs against difficult targets. We introduce a computer-guided platform that generates fully-human high affinity Abs against pre-selected epitopes on virtually any target. It allows efficient and rapid design of Abs against GPCRs and ion channel, species cross reactive Abs, bispecific Abs, and Abs against cryptic epitopes.


KEYNOTE PRESENTATION

15:35 RG7787 - A Cytolytic Fusion Protein Based on a De-Immunised Variant of Pseudomonas Exotoxin (PE)

Klaus BossletKlaus Bosslet, Ph.D., Head, Discovery Oncology, Roche Pharmaceuticals, Penzberg

Development of immunotoxins into actual drugs has been hampered by their immunogenicity and off-target toxicity, particularly vascular leak syndrome. Together with Ira Pastan’s lab at NCI we have developed a new cytolytic fusion protein format that is de-immunized and has much reduced off-target toxicity. Cell viability assays show that RG7787 has similar cytotoxic potency in a variety of cell lines as well as similarly strong efficacy as the immunogenic Mesothelin targeted PE38 from NCI (SS1P) even in slow growing tumour xenograft systems.


16:05 Creating Focused Libraries for Protein Engineering

Andrew Henry, Principal Scientist, Chemical Computing Group
Protein engineering plays a pivotal role in modulating the function, activity and physical properties of biologics. Representative strategies employed in protein engineering include directed evolution and rational protein design. Although both approaches are effective at identifying and optimizing protein therapeutic candidates, efficient search and evaluation of an excessively large sequence design space becomes challenging and requires multiple experimental rounds to reasonably assess the sequence space. Here we have developed a computational approach which predicts mutation probabilities for given residue sites in specified sequences. In assessing the probabilities at given residue sites, the sequence search space can be efficiently sampled to design and produce focused mutant libraries.
 

16:20 Sponsored Presentation (Opportunity Available) 

16:35 Refreshment Break in the Exhibit Hall with Poster Viewing


PRECLINICAL DEVELOPMENT AND CLINICAL VALIDATION

17:15 COVA322: A Novel Bispecific TNF/IL-17A Inhibitor for the Treatment of Inflammatory Diseases

JulianBertschingerJulian Bertschinger, Ph.D., CEO, Covagen

We present the discovery and preclinical development of COVA322, a potent bispecific TNF/IL-17A inhibitor which is about to enter clinical trials. COVA322 consists of an anti-IL-17A Fynomer fused to a fully human anti-TNF antibody and exhibits excellent biophysical properties. COVA322 was produced under GMP conditions with a yield of 3.3 g/l and was well tolerated in preclinical safety studies.

17:45 Preclinical and Clinical Developments with Nanobodies

HildeRevetsHilde Revets, Ph.D., Senior Research Fellow, Ablynx NV

Nanobodies are protein therapeutics based on the smallest functional fragments of naturally-occurring heavy-chain antibodies and enable straight-forward multimeric drug targeting across several formats and target classes. Examples from our drug pipeline candidates in clinical and preclinical development show that this formatting flexibility allows fine-tuning of valency, avidity, specificity for two or more targets, mechanism of action and half-life. In combination with favorable physicochemical properties, the Nanobody platform has the potential to bring biologics therapy beyond what’s possible with antibodies and will be exemplified by the development of ALX-0171, an inhaled Nanobody for the treatment of Respiratory Syncytial Virus infection in infants.

18:15 Discovery and Development of Human Bispecific Antibodies with Potent Anti-Tumour Activities

TonLogtenbergTon Logtenberg, Ph.D., CEO, Merus

This presentation will describe the use of a platform technology for the generation and high-throughput functional selection of heterodimerized human bispecific antibodies sharing a common light chain. These products, specific for combinations of receptor tyrosine kinases showed superior tumour cell killing activity, whereas CMC at 2000L scale was reminiscent of regular IgG antibodies. First-in-patient studies are planned in 2015.

18:45 End of Optimisation & Development



Speaker BiographiesDownload Brochure | Register