The Canadian Protein Engineering Network

1999-2000 ANNUAL REPORT

Protein discoveries for the new millennium CONTENTS

Chair's Perspective 1

Message from the Network Leaders 2

Network Overview 4

Research Program Overview 5

Profiles of our Success 13

Current Industrial Projects 15

PENCE Initiatives 17

Benefits to Canadians 17

Celebrating our Scientific Excellence 18

Extracts from Financial Statements 20

The PENCE Network 21

750 Heritage Medical Research Centre Edmonton, Alberta, CANADA T6G 2S2 Ph: 780/492-8851 Fax: 780/492-6995 email: [email protected] www.pence.ca CHAIR'S PERSPECTIVE

PENCE has during the past year been using its experience to prepare for the future in view of the exit requirements for NCEs in their last period of support. Bob Hodges and his colleagues worked hard to determine how much income a protein research network could achieve from commercialization of the research output to continue the network after the end of the third period of support. Their analysis clearly showed that there was no clear path with the existing institutional structure by which the basic research networks in the biosciences could be sustained by income from commercialization of the new knowledge produced from research and the private sector. Based on our own experience in commercialization, we have explored the possibility of setting up a national commercialization institute linked to the biosciences networks that could facilitate the transfer of new knowledge from basic research to potential commercial application. In discussion with governments, the private sector and many scientists in the biological sciences such an institutional innovation is needed if we are to meet the commercialization objectives set by the government for basic research. If this can be established, the network NCEs can focus on keeping up with the exponential growth in new opportunities in fundamental research. This is enormously important for research in protein structure and function. PENCE has, therefore, two key objectives for the future:

1. Putting in place with other NCEs in the biosciences and the private sector, a non profit institute for commercialization which we have presented as CNBiocom. 2. Defining the new area of basic protein research that could make use of the network structure that has been built by PENCE to work in a sector of proteomics.

With Bob Hodges stepping down as the leader of PENCE, Steve Withers has taken on the task of providing the scientific leadership for these new developments in research. Bob Church leads the commercialization development in collaboration with other board members and the entrepreneurial work of Graeme Macaloney in the PENCE office. During all these changes, the work of the staff, the board members, and the members of the PENCE network has been outstanding.

We could not have been able to define the issues as clearly as we have without the leadership of Bob Hodges. He made a key contribution to these developments and I am very grateful for his contributions. Steve Withers has followed in the tradition of Bob and the late Michael Smith in providing leadership for the value of the NCE concept as a national network in basic protein research. Mike Smith was always concerned that because of the commercialization pressures, PENCE would lose its focus and base in basic research. He fully supported our approach to restructure PENCE to restore the basic research focus and reduce the steering effect of commercialization, but that in doing this, we should establish a national institution that creates synergistic balance between the fundamental research and commercialization. He was in full support of the approach we are taking. If we can achieve these objectives, it will be a tribute to Mike and his contribution to the fundamental research in biosciences in Canada and starting one of the very high quality NCEs in the biosciences.

J.Fraser Mustard, Chair, Board of Directors

1 Message from the NETWORK LEADERS

PENCE Inc., as a result of its Phase III Strategic Plan, was awarded 7 years of additional funding at a level of $18.7 million for the first 4 years (1998-2002), with subsequent funding (2003-2005) to be determined later. The second year of Phase III (April 1, 1999 to March 31, 2000) was another successful year for PENCE. A $4.5 million grant from the NCE, attracted $2.26 million in cash contributions from non-NCE sources. Researchers published 196 scientific articles and filed 7 non-disclosure agreements and 6 patent applications. Eight licenses were granted to, or were under negotiation with, industry. PENCE also negotiated equity in two start-up companies -Molecular Templates Inc. and Converzyme Inc. In addition, Exella Ventures Inc., a start-up seed venture capital Dr. Robert Hodges, company created in partnership with the Canadian Genetic Diseases Network CEO/Scientific Director (June 2000) (CGDN) and the Canadian Bacterial Diseases Network (CBDN), was incorporated. The lead partner, CGDN, is presently seeking funding for Exella.

The past year has seen much change and progress within the PENCE National Business Centre in terms of personnel changes and strategic planning, with a view to mapping out the next 5 years and beyond for PENCE research and commercialization activities. In February 2000, Taryn Campbell our Manager of Marketing and Communications departed PENCE for new horizons. On the Board we said goodbye to Julia Levy of QLT Phototherapeutics Inc., whose energies were needed closer to home to oversee QLT's rapid growth and product development.

Steve Withers, In December of 1999, Dr. Robert Hodges announced his intention to step down CEO / Scientific Director (July 2000) as the PENCE Inc. CEO and Scientific Director, ending his 5-year tenure, effective June 30, 2000. Bob's dedication and contributions to PENCE have been enormous. Under his leadership PENCE was incorporated and renewed for Phase III, receiving the highest funding of any network in the NCE program. PENCE partnerships with industry also reached new heights as is evident in this and previous years statistics. Bob has taken a leave of absence to carry out research at the University of Colorado Health Science Center.

Dr. Stephen Withers was identified after an extensive recruitment to replace Dr. Hodges. Steve will act as interim Scientific Director and CEO, assisted by Brian Sykes, Director of the PENCE Alberta Centre. Steve is a member of both the and Biochemistry Departments at the University of British Columbia, where he holds the Khorana Chair of Biological Chemistry. He is a founding Dr. Graeme Macaloney, COO/Network Manager member of PENCE and has served on the Board of Directors for the past 4 years.

2 2000 ANNUAL REPORT In reviewing the future of PENCE, the Board and Management followed on from last year's Task Group meetings with Principal Investigators, Board members, Management, and key outside stakeholders to capture the review and planning process in a "Strategic Plan: Future Vision for PENCE and the Life Science NCEs". This was crafted with the input of Gordon MacNabb O.C., P.Eng., past federal government Deputy Minister, past President of NSERC and past President of PRECARN. Key recommendations from this were the creation of an International Research Advisory Committee (IRAC), the re-focusing of PENCE as a proteomics oriented research network, and the creation of a new national commercialization network involving other life science NCEs.

The mandate for IRAC is to advise PENCE leadership on the network's future focus in protein research and to position it at the leading edge internationally. IRAC is a critically important committee because it uses an independent, peer review approach to ensure that PENCE research is at the forefront internationally. IRAC members are: Dr. Cyril Kay, Chair, (Canada), Dr. Michel Chrétien, (Canada), Dr. Chris Dobson, (United Kingdom), Dr. Kurt Drickamer, (United Kingdom), Dr. Jack Greenblatt (Canada), Dr. Robert Hodges, (Canada), Dr. Howard Schachman, (United States), Dr. Michael Smith (Canada). The development of the proteomics initiative awaits the capable direction and leadership of Steve Withers.

The commercialization initiative has begun with a long-term strategy of engaging a variety of private sector, NCE and government stakeholders - communicating the benefits of a new national commercialization initiative and receiving feedback. The ultimate goal is to obtain federal government, provincial government and private sector funding for the initiative and spin it off as a separate but linked agency to PENCE and the life science NCEs.

Although many changes have occurred and will continue to do so, some basic concepts remain, for PENCE: protein research will remain at the forefront of biotechnology; excellence of science and networking of strategic discovery research from across Canada will enhance the development of new products, services and technologies; training and retaining personnel in Canada is key; and bundling of technologies from multiple institutions will enhance the technology transfer process, company creation and venture capital investment in Canadian technology.

Finally on a sad note, we wish to pay tribute to the recently deceased co-founders of PENCE Inc., Michael Smith, Nobel Laureate (October 4, 2000) and Larry Weiler, former head of the Chemistry department at UBC (April 28, 1999). It was through their efforts that the PENCE proposal was assembled, and Michael, of course, served as the leader of PENCE during its first four year term. They are both greatly missed. November 2000

Bob Hodges, Steve Withers, Graeme Macaloney, CEO / Scientific Director CEO / Scientific Director COO / Network Manager (June 2000) (July 2000)

3 NETWORK OVERVIEW

The PENCE Network

PENCE Inc.'s PENCE Inc. (The Canadian Protein Engineering Network) is a dynamic network of top researchers specializing in the study of protein technologies. As an incorporated, non-profit, discovery strong commitment research and commercialization company, PENCE represents a unique partnership of 18 universities, research hospitals and research institutes across Canada. PENCE boasts globally to scientific competitive protein technologies and innovative research ideas for new protein products, pharmaceutical therapeutics and biotechnological research tools. Our industrial partners benefit excellence coupled from some of the best protein/peptide expertise in the world provided by the PENCE network. with market driven Created in 1990, through the federal government Network of Centres of Excellence Program, commercialization PENCE will have invested some $64 million in basic and strategic protein research by 2002. Phase III of the research program will provide funding strategies allows us to a level of $18.7 million for the first four years (1998- 2002). Next year PENCE will conduct an international PENCE Inc. to bring innovative peer reviewed 'mid-term review'. For this we will be The Canadian Protein Engineering Network critically examining the content, progress and direction research for the research program. This will ensure that for the remainder of Phase III and Phase IV (2003 - 2005) techniques to the PENCE is positioned as a leading player in the evolving National Business Centre Alberta Regional Centre area of proteomics. pharmaceutical, The PENCE network is structured with four PENCE chemical and Regional Centres (Figure 1) located in Vancouver B.C. Regional Centre Quebec Regional Centre (University of British Columbia), Edmonton (University biotechnology of Alberta), Toronto (University of Toronto) and Montréal (Université de Montréal). The National Business Centre, Ontario Regional Centre industries as well in Edmonton, serves as the main business entity for administration of the network and commercialization as to specialized of the protein technologies developed within the segments of the PENCE network.

health care What is Protein Engineering?

industry. Proteins are found in all living organisms. They are Figure 1 composed of units of amino acids linked together in a long string. The way each string folds determines the function of a protein. Proteins can act as enzymes, hormones, chemical messengers and receptors. A large number of diseases are caused by imbalances in proteins, either because a specific protein is absent, defective, or present in too small or too great a quantity. Protein engineering applies the knowledge of the structure and function of proteins to the design of new and improved therapeutics, passive and active vaccines, diagnostics, industrial, environmental and agricultural products and enzymes and research tools. What is Proteomics?

The term 'Proteome' was coined in 1994 as the linguistic equivalent to the concept of the genome, and describes the complete set of proteins that is expressed and modified in the lifetime of a . Proteomics, or functional genomics therefore, is the large-scale study of the proteome using technologies including protein expression and separation, characterization of protein structure and function, and rational drug design. Each of these proteomic areas requires data management and bioinformatics to manage the large volumes of data and to develop value added knowledge that may ultimately lead to new products, services or technologies.

4 2000 ANNUAL REPORT RESEARCH PROGRAM OVERVIEW

PENCE' s research program is divided into seven themes, spearheaded by a top researcher in that field of study. Each theme is further subdivided into separate projects made up of multidisciplinary teams of the top researchers in their field from across Canada. Many have achieved international standing, awards, fellowships and some are officers of the Order of Canada. An overview of the seven research themes follows.

Theme A: Receptors and Signal Transduction Future Treatments for Allergies, Inflammation and Cancer

Leader: John Schrader, BioMedical Research Centre , University of British Columbia

Research Team: Eric Ball (University of Western Ontario), Gary Brayer (University of British Columbia), Ian Clark- Lewis (University of British Columbia), Robert Hodges (University of Alberta), Lewis Kay (University of Toronto), Emil Pai (University of Toronto), (Mt. Sinai Hospital), Jim Rini (University Protein of Toronto), Brian Sykes (University of Alberta), Mike Tyers (Mt. Sinai Hospital), Alice Vrielink (McGill University), Hermann Ziltener (University of British Columbia). discoveries Overview of Theme A Research Projects for the new Development of Inhibitors of IL-5 Action Project Driver: John Schrader, University of British Columbia millennium One objective of this research is to identify as leads for inhibitor design, peptides that target the extracellular domain of the IL-5 receptor -chain and inhibit either its interaction with IL-5 or its ability to interact with the ßc receptor subunit. This part of the project involved collaboration with Aventis.

A second objective is to characterize the three-dimensional structure of the intracellular domain of IL-5R receptor and define the structural basis of the association with the critical signaling molecule, JAK-2 kinase that we previously demonstrated. We aim to validate the interaction of intracellular domain of IL-5R receptor and JAK-2 kinase as a target for compounds which will block the ability of IL-5 to generate and activate eosinophils and suppress their apoptotic death. This part of the project initially involved a collaboration with Novartis.

The main commercial goals of this project are to develop peptide lead compounds as IL-5 antagonists and to develop an assay for screening compounds with a novel mechanism for inhibiting IL-5 action. The aim is to develop a drug that blocks the pathogenic mechanisms underlying the chronic changes in bronchial asthma. The project is currently seeking new industrial partners.

Modular Protein-Protein Interactions in Signal Transduction-Structure, Function and Inhibition Project Driver: Tony Pawson, Mt. Sinai Hospital

The research in this project includes three subprojects: 1 analysis of modular adaptor proteins and their binding partners 2 determine the structure and function of receptor Mck10, identify its physiological ligands 3 analysis of protein interactions and the cell cycle using yeast as a tool

The main diseases targeted are breast, ovarian and brain cancers as well as specific leukemias. An unnamed industrial partner, may get involved in the research to investigate specific inhibitors for serine/threonine protein kinases.

5 Novel Therapeutics for Inflammatory Diseases Project Driver: Ian Clark-Lewis, University of British Columbia

The research involves characterization of peptides corresponding to the N-terminal region of chemokines. As therapeutics, small molecules are preferable, therefore studying peptides could provide leads. The importance of the N-terminal domain in chemokine function was demonstrated and we found that SDF and vMIP2, a viral derived chemokine, bound to one of the chemokine receptors. Moreover a SDF peptide was biologically active but was more active as a dimer. The research investigated the basis for this property.

In a separate project we completed the structure of the allergy associated chemokine, eotaxin. A study of the structure function studies involving engineering non-natural disulfide-bridges in IL-8 was completed. Several of these high resolution X ray structures have been recently finished which should allow further examination of the local structural effects of these modifications.

Structural Studies of Cyclic Nucleotide Phosphodiesterases Project Driver: Alice Vrielink, McGill University

Cyclic AMP and cyclic GMP are major secondary messenger molecules that affect cell growth and proliferation through signal transduction pathways. The concentrations of cyclic nucleotides are determined by the rates of their synthesis and degradation. The presence of cyclic nucleotide phosphodiesterases (PDEs) (the enzymes responsible for Cyclic AMP and Cyclic GMP degradation) can be used as a method of controlling the messengers thereby controlling cell growth. The objective of this project is to determine the 3 - dimensional structures of PDEs and to correlate structural properties with functional assays involving enzyme regulation and substrate/inhibitor binding. Commercially, this research has applications for the design and development of inhibitors for the treatment of asthma and other inflammatory diseases. A major partner in this research is Merck-Frosst whose focus is the anti-inflammatory field in general, and specifically this enzyme target.

Theme B: Proteinases of Disease: Structure-Function Database of Therapeutic Targets

Leader: Dr. Nabil Seidah, Institut de Recherches Cliniques de Montréal (IRCM)

Research Team: Michel Chrétien (Loeb Health Research Institute), Mirek Cygler (BRI/McGill), Peter Davies (Queen's University), John Elce (Queen's University), Zhongchao Jia (Queen's University), Claude Lazure (IRCM), Robert Ménard (BRI/McGill), John Mort (McGill University), Feng Ni (BRI/McGill), Andrew Storer (BRI/McGill).

6 2000 ANNUAL REPORT Overview of Theme B Research Projects

Pharmacological and Medical Application of Precursor Convertases Project Driver: Nabil Seidah, Institut de Recherches Cliniques de Montréal (IRCM)

The main objective of this project is to identify the structure and function of precursor (PC) convertases including Furin, PC5, PC7, PC1 and PC2/7B2 using NMR and X-ray crystallography. The results of the research provides novel targets for drug design for diseases such as Alzheimers, viral infections, restenosis and other diseases. The industrial partner collaborating on this research is T2C2, where a spin-off company (Converzyme Inc.) has been setup.

Regulatory Cysteine Proteases: Dipeptidyl Peptidase I and Homologs Project Driver: John Mort, McGill University

Cathepsin C (also known as dipeptidylpeptidase I) is a cysteine protease which plays a role in normal physiological processes as well as pathological conditions. This aminodipeptidase is a potential target for the development of immunotherapeutic agents that function through the control of granzyme activation and target cell apoptosis. Our research program follows on from our previous work on several other members of this rapidly expanding family of cysteine proteases, and will lead to a structure-function database which will be used to develop inhibitors of cathepsin C. Results of this research should have applications in the treatment of inflammatory and autoimmune diseases, arteriosclerosis, leukemia, multiple sclerosis, and myasthenia gravis. Another interesting application may be in organ transplantation where the ability to suppress the immune Protein system is required to prevent organ transplant rejection and graft versus host disease.

Structure-Function Studies on Calpain and the Design of Inhibitors discoveries Project Driver: John Elce, Queen's University

The purpose of this research is to determine the structure of calpain with and without for the new bound calcium and inhibitors and to explain the regulation of its activity. The results will be used in the search for, and rational design of, specific calpain inhibitors suitable millennium for clinical use. We have recently succeeded in obtaining the structure of calpain in the absence of calcium and our efforts are now aimed at obtaining structures of calpain covalently bound to various inhibitors, in the presence and absence of calcium. This is a difficult task, owing to the rapid aggregation and autolysis of calpain in the presence of calcium.

Many major pharmaceutical companies are searching for specific, clinically acceptable calpain inhibitors for the development of drugs related to stroke and other neuro- degenerative conditions. Abnormal activation of calpain is implicated in disorders such as cerebral ischemia, cardiac ischemia, Alzheimer's disease, myocardial infarction and platelet aggregation.

The work has received major support from Warner-Lambert Canada, and Hoechst Marion Roussel have also supplied inhibitors for crystallization trials. Additional work involves structure-function studies of the EF-hands and other mutations in calpain, based on the newly available structure. A transgenic mouse lacking calpain has been generated, and forms the basis of extensive cell biology studies on calpain function in vivo.

7 Theme C: Medical Applications of Dimerization Technology

Leader: Dr. Randy Irvin, University of Alberta

Research Team:. Dave Bundle (University of Alberta), Jean Gariépy (Ontario Cancer Institute/University of Toronto), Mark Glover (University of Alberta), Robert Hodges (University of Alberta), Bruce Lennox (McGill University), Maureen O'Connor-McCourt (BRI/McGill), Cyril Kay (University of Alberta), Brian Sykes (University of Alberta).

Overview of Theme C Research Projects

Biosensor Instrumentation, Diagnostic Applications Utilizing Heterodimer Coiled-Coil Technology Project Driver: Robert Hodges, University of Alberta

The main objective of this research is the development of an inexpensive, robust biosensor coupled with the versatility and design features of our coiled-coil heterodimerization technology which should eliminate the barriers to the implementation and use of biosensors for a wide range of applications.

The biosensor is a newly developed and patented device, which operates on the principle of electrochemical detection of receptor-ligand interactions. The main features of this unique system are a highly ordered lipid monolayer chemically grafted to a gold electrode surface along with a capture peptide. Signal generation is triggered by a ligand delivery peptide which complexes with a capture peptide forming a heterodimeric coiled-coil in the lipid monolayer. The utility of the heterodimerization technology for immobilization of ligands on surfaces and detection of protein interactions with immobilized ligands is being applied to various proteomics applications. Helix BioPharma has licensed technologies created by this research to develop biosensor products for a wide range of medical applications through their subsidiary, Sensium Technologies Inc.

Screening of Synthetic Peptide Libraries for Mucin Ligands Project Driver: Jean Gariépy, Ontario Cancer Institute

Present and future drug delivery strategies in the area of cancer therapeutics all hinge on the development of small ligands able to target and deliver cytotoxic and diagnostic moieties to cancer cells. In this project, we plan to identify small peptide ligands able to target breast, as well as other epithelial cancer cells, using combinatorial peptide libraries and high throughput screening approaches. Our group is focusing on finding peptide ligands binding to the mucin MUC1 tandem repeat, an important and structurally well-defined tumour-associated antigen.

8 2000 ANNUAL REPORT Conformationally Defined and Constrained Peptide Combinatorial Libraries for Drug Discovery and Development Project Driver: Robert Hodges, University of Alberta

Combining the power of combinatorial library selection procedures with the design of template molecules able to confer particular structural constraints on a class of molecules is a rational way to identify ligands with novel receptor binding properties for drug discovery programs. A two-stranded -helical coiled-coil has been used as a template to display a library of sequences on the solvent exposed face of the -helix in this model system. This library contains about 1.9 million compounds for evaluation.

Once a sequence has been identified in the library, a lead compound consisting of a monomeric peptidomimetic with the identified sequence can be designed and synthesized. The peptidomimetic lead compound is then evaluated for potential therapeutic use (excellent stability and resistance to proteolysis) or the molecular coordinates can be employed in a rational, structure-based drug development program.

A new start-up company, DDL (Drug Discovery Libraries Inc.), is being formed to provide this service to existing pharmaceutical and biotechnology companies to enhance their drug discovery programs. The company's major focus will be on drug discovery in niche areas using this technology.

DeNovo Design of Structural Motifs for Protein Engineering Applications Project Driver: Maureen O'Connor-McCourt, BRI/McGill University

Coiled-coils play significant roles in the control of a large variety of cellular responses, Protein particularly in the complex signaling cascades that modulate responses to a wide range of environmental and cellular growth factors . This project is examining various coiled- coil systems in order to design and generate molecular biology reagents that can discoveries effectively use coiled-coils to control the specific dimerization (as either homodimers or specific heterodimers), or oligimerization of different proteins for a variety of protein engineering applications. for the new

millennium

Theme D: Design and Engineering of Peptides and Proteins for Biotechnology Applications

Leader: Peter Davies, Queen's University, Kingston, Ontario

Research Team: Research Team: Robert Hodges (University of Alberta), Randy Irvin (University of Alberta), Zongchao Jia (Queen's University), Cyril Kay (University of Alberta), Ron McElhaney (University of Alberta), Brian Sykes (University of Alberta), David Wishart (University of Alberta).

9 Overview of Theme D Research Projects

Design & Applications of Helical Antifreeze Peptides Project Driver: Peter Davies, Queen's University

Antifreeze proteins (AFP) are the reason fish can survive cold temperatures. AFPs bind to the surface of a seed ice crystal and prevent its growth. The potential applications would be in the frozen food industry (as an additive to frozen food), crop protection (to increase frost and freeze tolerance in plants) and various biomedical applications such as cryopreservation of blood products, and the use of AFP as an adjuvant in cryosurgery. A research collaboration and a license are ongoing between A/F Protein Inc., Queen's University and PENCE/University of Alberta.

Antibacterial Peptides Project Driver: Randy Irvin, University of Alberta

There is a pressing need for new classes of antibiotics due to the emergence of wide- spread antimicrobial resistance, which has threatened the effectiveness of all existing classes of antibiotics. The strategy of this project is to target cyclic peptides related to Gramicidin S (GS), a well studied membrane active antibiotic that is currently of limited clinical use due to toxicity difficulties. The structure-activity-relationship profile of GS has been modified to generate a series of novel antibiotics with decreased toxicity and enhanced antimicrobial activity profiles for selected clinical indications. Micrologix Biotech Inc. has partnered with PENCE to develop the technology further for the marketplace.

Theme E: Microbial Enzymes for Industry

Leader: Grant Mauk, University of British Columbia

Research Team: Donal Leech (Université de Montréal), Grant Mauk (University of British Columbia), Mike Paice (Pulp and Paper Research Institute of Canada (PAPRICAN)), Jeff Tolan, (Iogen) and Theresa White, (Iogen).

Overview of Theme E Research Projects

Recombinant Laccase for Pulp Delignification Project Driver: Mike Paice, Pulp and Paper Research Institute of Canada (PAPRICAN)

The goal of this work is to obtain a laccase variant with increased reduction potential, thermal stability and pH range, and to identify new mediators and processes that improve the effectiveness of laccase in the degradation of lignin. The project is aimed at producing recombinant laccase and improved laccase mediators for pulping and bleaching of kraft pulps, which will result in lower costs compared to conventional bleaching. Spin-off applications in other industries include textiles and effluent treatments. PAPRICAN (the Pulp and Paper Research Institute of Canada based in Montréal) is a major partner in this initiative and works closely with PENCE researchers.

10 2000 ANNUAL REPORT Theme F: Carbohydrate-based Technologies

Leader: Tony Warren, University of British Columbia

Research Team: Gary Brayer (University of British Columbia), Charles Haynes (University of British Columbia), Doug Kilburn (University of British Columbia), Lawrence McIntosh (University of British Columbia), Maureen O'Connor-McCourt (BRI/McGill), Peter Ottensmeyer (Ontario Cancer Institute/University of Toronto), Steve Withers (University of British Columbia), Jim Rini (University of Toronto), David Rose (Ontario Cancer Institute/University of Toronto, Harry Schachter (Hospital for Sick Children/University of Toronto).

Overview of Theme F Research Projects

Enzymatic Synthesis of Oligosaccharides Using Engineered Glycosidases Project Driver: Steve Withers, University of British Columbia

The focus of this project is on further developing a patented platform technology, "Glycosynthases" (specifically mutated glycosidases that make, but do not hydrolyse, glycosides) to synthesize oligosaccharides in high yields and from inexpensive substrates. Protein Oligosaccharides have various applications such as additives in infant milk formula that function as anti-infective agents identical to those in mother's milk, as anti-ulcer agents, and as therapeutics for middle ear infections. The collaborative partner is discoveries NEOSE Technologies Inc.

3 - D Structure Determination of Glycosyltransferases and Glycosidases for the new as a Tool in the Design of Glycotherapeutics Project Driver: Jim Rini, University of Toronto millennium Glycoconjugates play important roles in many normal and pathological cell-cell interactions, including embryogenesis, inflammation, immune reactions, metastasis, viral and bacterial infections, etc. Inhibitors of these processes may therefore have therapeutic potential as anti- inflammatory, anti-viral and anti-metastatic agents. The collaborative partner for this project is GlycoDesign Inc., a PENCE spin-off company.

Structure-Function and Applications of Carbohydrate-Binding Domains Project Driver: Charles Haynes, University of British Columbia

Research involves determining the structure and function of carbohydrate binding domains and development of related applications. The commercial potential of this platform technology in cellulose binding domains has been exploited in licenses to Novo Nordisk A/S, in the field of textiles and detergents, and to CBD Technologies Inc. in all other fields of use. Some of the applications of this technology include: targeting of enzymes to selected regions of their substrates, enzyme immobilization, and purification of CBD-fusion proteins. CBDs may also be used as probes to characterize fibre properties for pulp and paper applications, and to obtain insights into factors limiting biomass conversion.

11 Theme G: Bioinformatics

Leader: Brian Sykes, University of Alberta

Research Team: Suzanne Fortier (Queen's University), Janice Glasgow (Queen's University), John Gunn (Université de Montréal), Lewis Kay (University of Toronto), Francois Major (Université de Montréal) Lawrence McIntosh (University of British Columbia), Enrico Purisima (BRI/McGill), Chris Upton (University of Victoria), Benoit Roux (Université de Montréal), and David Wishart (University of Alberta).

Overview of Theme G Research Projects

NMR Technology and Biomolecular Recognition Project Driver: Lawrence McIntosh, University of British Columbia

The objective of this research is to develop and apply new methods in NMR spectroscopy towards understanding how proteins recognize and bind ligands ranging from small molecules to other proteins. An understanding of the molecular basis for this recognition is central to the fields of protein engineering and drug design. In particular, recent developments in techniques for the acquisition and computer processing of NMR data, combined with new biosynthetic methods for selective isotopic labeling, are allowing the study of much larger proteins and protein-complexes with increasing speed and accuracy. A controlled access internet site has been set up for free distribution of newly developed NMR software for automatic spectral assignments to PENCE researchers. In addition, new NMR pulse sequences necessary for the acquisition of data are distributed freely to well over 100 laboratories worldwide.

Bioinformatics and Structure-based Drug Design Project Driver: David Wishart, University of Alberta

Bioinformatics is an area of information technology concerned with the handling and analysis of protein and DNA sequence data. Structure-based drug design is a computational technique, which uses 3-D structures of putative ligands and receptors to design and test new drug leads. The focus of this project is to create software that will make research in protein chemistry and protein-based drug discovery more productive. Industrial partners include BioTools Inc., Molecular Mining Inc., CERCA and Merck Frosst.

12 2000 ANNUAL REPORT PROFILES OF OUR SUCCESS

Established Companies

PENCE technologies have played an integral part in the development of several successful companies such as BioTools Inc., Cytovax Biotechnologies Inc., GLYCODesign Inc., and Sensium Technologies Inc. A brief overview of each follows.

BioTools Incorporated is a privately held biotechnology company dedicated to producing quality bioinformatics software. BioTools' three primary products, PepTool, GeneTool, and ChromaTool, are designed to facilitate leading edge technology by providing a powerful and intuitive interface to access sequence data and analytical tools. BioTools also offers consulting and contractual software development services; allowing clientele to take advantage of BioTools' talented programming staff to create a product tailored to their needs.

Cytovax Biotechnologies Inc. is focusing on the development and commercialization of vaccines and therapeutic products for the prevention and treatment of infectious diseases. Cytovax's proprietary Anti-Adhesin Platform Technology is being used to develop peptide vaccines and monoclonal antibodies to prevent and treat a wide range of infectious agents. Cytovax has signed a licensing and co-development agreement with BioChem Pharma Inc. for its first two bacterial targets based on this technology. Protein

GLYCODesign Inc. a Canadian biopharmaceutical company is dedicated to improving human health by developing novel therapeutic strategies and drug candidates for life- discoveries threatening diseases such as cancer, infectious diseases, inflammation, and cardiovascular diseases, through its unique glycobiology research platform. GLYCODesign's platform technology incorporates advanced computational techniques for the new to identify and accelerate the design, optimization and development of glycotherapeutics.

Sensium Technologies Inc. continues to pursue the development of Helix BioPharma millennium Corp's proprietary molecular sensing technology licensed from PENCE, University of Alberta, and McGill University. This remarkable technology is being used for the identification and study of drug targets and new diagnostics. Sensium intends utilizing this new valuable technology to advance proteomic research for itself and Helix BioPharma Corp. and other pharmaceutical companies.

13 Start-up Companies

CONVERZYME INC. Converzyme Inc., an evolutionary Canadian research & development company, is an outstanding example of how two Canadian academic institutions, Institut de Recherches Cliniques de Montréal and LOEB in Ottawa, the Protein Engineering Network of Centres of Excellence and T2C2 , a venture capital limited partnership, can come together and create a leading edge research company.

Converzyme Inc. is a leading edge research company with a drug discovery strategy based on a portfolio of proprietary serine proteases, the proprotein convertases. The protein convertases are potential drug targets for major human diseases including Alzheimer's disease, restenosis, cancer metastasis and cholesterol/fatty acid disorders.

Converzyme has obtained an exclusive license to commercialize all intellectual property developed by the Institut de Recherches Cliniques de Montréal in the laboratories of Dr. Nabil G. Seidah and Dr. Michel Chrétien, pertaining to proprotein convertases. This research has been funded in part by PENCE under project B1 - Pharmacological and Medical Applications of Precursor Convertases. This research has led to two issued patents and three patents applications, to date.

Currently, PENCE and Converzyme are continuing the research effort at the IRCM and LOEB, funding several PENCE investigators. The goal of this research is to develop treatments to target proprotein convertase family members implicated in restenosis and Alzheimer's, in particular. The markets for the treatment of these diseases are currently undefined with respect to remedies.

MOLECULAR TEMPLATES INCORPORATED Molecular Templates Incorporated (MTI) was created by Dr. Jean Gariepy, with assistance from the Technology Transfer and Research Business Development Office of the University Health Network, and the PENCE Business Development Office. Dr. Jean Gariepy is a principal investigator for PENCE, as well as a Senior Scientist at the Ontario Cancer Institute of the University Health Network, and a at the University of Toronto. Within MTI Dr. Jean Gariepy holds the Chief Scientific Officer position. At MTI he will be assisted by Dr. Leigh Revers (Scientific Operating Officer), and Dr. David B. Shindler (President).

MTI recently received an initial investment from a syndicate formed by Milestone Medica, Sunnybrook Working Ventures Medical Breakthrough Fund, and a private investor.

The mission of Molecular Templates Inc (MTI) is to generate an entirely new and effective class of cancer therapeutics. Molecular Templates Inc. employs a combinatorial approach to modify a powerful naturally occurring cytotoxin in order to give it the ability to selectively target and kill different cancer cell types. Unlike present day chemotherapeutic agents which have minimal tissue specificity and thus severe side effects, MTI's toxins will be tissue specific, giving a significant advantage over competing therapies. The technology also has other therapeutic and diagnostic applications. MTI will focus initially on developing therapeutic agents for breast and prostate cancer.

14 2000 ANNUAL REPORT CURRENT INDUSTRIAL PROJECTS

PENCE attributes much of its success to key strategic partnerships with biotechnology and pharmaceutical companies in a variety of different research areas. Overall, collaborations with industry have benefited PENCE through joint research projects between industry, PENCE and PENCE institutional partners. A brief overview of select projects is provided.

Our partners, major players in the industry, have included: A/F Protein Inc. Hoechst Marion Roussel AltaRex Inc. IBIS Pharmaceuticals Inc. AstraZeneca Iogen Corp. Bayer Biological Products Merck Frosst Canada Inc. BioTools Inc. Micrologix Biotech Inc. Biomira Inc. NEOSE Technologies Inc. Cangene Corporation Novartis Pharmaceuticals Inc. CBD Technologies Inc. Novo Nordisk Inc. Protein Converzyme Inc. Cytovax Biotechnologies Inc. Osprey Pharmaceuticals Inc. discoveries Glaxo Wellcome Inc. Pasteur Mérieux Connaught Ltd. Sensium Technologies Inc. GLYCODesign Inc. for the new Helix BioPharma Corp. Warner-Lambert Canada Inc.

millennium A/F Protein Inc. A research grant with Dr. Davies (Queen's University) and collaborators to determine the NMR and X-ray structures of helical anti-freeze proteins (AFP) as well as methods for the production of stabilized helical platform AFPs.

AstraZeneca A research grant to Dr. Kay (University of Toronto) for a three-year project on the development of NMR methods for the study of the structure, dynamics and thermodynamics of proteins and protein complexes. The specific focus will be on developing NMR approaches for the study of high molecular weight systems.

BioTools Inc. Initially, a PENCE start-up company, BioTools is now providing a research grant to Dr. Wishart (University of Alberta) and collaborators to develop technology that will enhance BioTools' existing technology pipeline. Research areas include: developing new methods to find remote sequence and structure relationships, predicting protein solubility, stability, and structure, data-mining techniques, and protein-ligand docking strategies.

CBD Technology Inc. / Novo Nordisk Inc. A research grant for Dr. Haynes (University of British Columbia) and collaborators, to determine the structure, function and potential modification of Cellulose-Binding Domains (CBDs) as they interact with various polypeptides.

Converzyme Inc. A research grant with Dr. Seidah (IRCM) and collaborators to determine the structure, function and potential drug targets of proprotein convertases.

15 Cytovax Biotechnologies Inc. The laboratories of Dr. Hodges and Irvin at the University of Alberta will focus on developing an anti-Pseudomonas synthetic peptide vaccine.

Glaxo Wellcome Inc. A research contract with Dr. Clark-Lewis (University of British Columbia) and collaborators to research inhibitors of the N-Terminal domain of the Chemokine/Receptor interface, using peptide analogs.

GLYCODesign Inc. A research grant with Dr. Rini (University of Toronto) and collaborators to focus on structure determination of glycosyltransferases and glycosidases as a tool in the design of glycotherapeutics.

Helix BioPharma Corp. / Sensium Technologies Inc. A collaborative research and development agreement and a licensing agreement to develop platform biosensor technology based on Dr. Hodges (University of Alberta) coil-coiled heterodimer system to create a novel biosensor, the "BIOSMART® card".

Hoechst Marion Rousel A contract with Dr. Ziltener's (University of British Columbia) lab to screen a number of compounds for the purpose of identifying IL-5R inhibitors.

IBIS Pharmaceuticals Inc. A three-year contract for a PENCE research project with Dr. François Major from the Université de Montréal. Dr. Major will be working on creating 3-Dimensional models of proprietary RNA sequences using his novel MC-SYM software.

Iogen Corp. A research grant for Dr. Mauk's (University of British Columbia) group to develop a class of enzymes called 'laccases' that break down lignin, a by-product in the pulp and paper industry. Iogen has hired a post-doctoral person to work in conjunction with Dr. Mauk's team.

Merck Frosst Canada Inc. A research grant with Dr. Vrielink (McGill) and collaborators to focus on phosphodiesterases (PDEs). Work is conducted on determining the X-ray and NMR structures for various PDEs.

Micrologix Inc. A collaborative research and development agreement and a licensing agreement with Dr. Hodges (University of Alberta) and collaborators to develop a group of cyclic anti- bacterial peptides to serve as new generation therapeutics.

NEOSE Technologies Inc. A research grant with Dr. Withers (University of British Columbia) and collaborators to focus on engineering glycosidases to turn them into synthetic enzymes capable of making oligosaccharides.

Novartis Pharmaceuticals Inc. A research grant with Dr. Schrader's lab (University of British Columbia) to focus on the identification of specific IL-5 targets.

Warner-Lambert Canada Inc. A contract research agreement exists with Dr. Elce (Queen's University) and collaborators to solve the crystal structure for a particular calpain.

16 2000 ANNUAL REPORT PENCE INITIATIVESINITIATIVES

Exella - A Potential Multi-Network Venture Capital Fund Spearheaded by the Canadian Genetics Diseases Network (CGDN), in partnership with the Canadian Bacterial Diseases Network (CBDN) and PENCE. Exella Ventures Inc., if successfully financed, will provide seed stage equity based financing to network start-up companies. Financing for Exella is presently being sought.

International Research Advisory Committee This committee of internationally recognized experts in the area of protein chemistry and biochemistry has been formed to provide advice and guidance to PENCE in positioning itself to remain at the leading edge of its field.

New Initiatives Fund The New Initiative Fund replaces the PENCE Seed Fund. The program receives contributions from industry that go to support new research and development initiatives. It serves to create new linkages and bring in new industrial partners to exploit technologies developed in the PENCE network.

PENCE Biotechnology Internships Through the Alberta Heritage Foundation for Medical Research (AHFMR) and the Biotechnology Human Resource Council (BHRC), PENCE has been able to provide valuable work experience for three University of Alberta MBA students in the marketing and technology transfer areas. At the same Protein time PENCE has benefited greatly from the energy and brain power of these keen, enthusiastic people.

Proteomics Task Group discoveries A new PENCE Proteomics Task Group has been formed to look at how PENCE may take a leadership role in creating a "Canadian Proteomics Initiative". Consisting of PENCE researchers, the task group will develop a long-term strategy for PENCE on this initiative. for the new

millennium BENEFITS TO CANADIANS

PENCE continues to implement a wide variety of programs to commercialize novel protein discoveries and technologies to benefit Canadian industry and the Canadian economy. In the past year, significant advances have been made in meeting our mandate of excellence in scientific research, networking across Canada, technology transfer, commercialization, and training of the next generation of creative investigators and business leaders.

The PENCE network has created over 1300 publications and 39 patents since its inception in 1990. Seventy percent of the publications were a result of collaborations with other researchers within and outside of the network. The PENCE network is proud of our highly skilled and trained personnel. PENCE provides a unique experience for trainees to work in multi-disciplinary teams, with both academic and industrial scientists. Since our inception in 1990 more than 200 trainees have completed their training, and are employed both in industry and academia world-wide.

Through the NCE program, PENCE Inc. has invested up to $20 million on leading edge equipment and facilities across Canada bolstering the country's overall research infrastructure. PENCE plans to constantly upgrade these facilities to maintain a "world-class" capability in protein engineering.

Our research scientists create many opportunities to commercialize PENCE technologies. The many start-up companies resulting from PENCE's activities are a vital source of job creation and opportunities for collaborative R&D. These companies also generate new products, services and technologies to better position Canada in the global biotechnology marketplace.

17 CELEBRATING OUR SCIENTIFIC EXCELLENCE

Dr. Dimitris Argyropoulos (McGill University, Pulp and Paper Research Centre) - elected a of the International Academy of Wood Science and was also made a Fellow of the Chemical Institute of Canada for his outstanding contributions to science.

Dr. Michel Chrétien (Loeb Research Institute) - 2000: a D.Sc (Honoris Causa) from Memorial University, Newfoundland, and the Actualité médicale, Médecins de mérite and Prix Galien. In 1999: a D.Sc (Honoris Causa) from the University of Guelph. The Henry Friesen Award and the PMAC Health Research Foundation Medal of Honor (now Canada's Research-based Pharmaceutical Companies, Rx&D).

Dr. Peter Davies (Queen's University) - Killam (as of January 1, 2000) and was awarded the Queen's University Prize for Excellence in Research.

Dr. Charles Deber (Hospital for Sick Children) - the 2000 Vincent DuVigneaud Award, from the American Peptide Society, which honors "outstanding achievements in peptide research". Dr. Deber's laboratory developed the program "TM Finder", software for prediction of membrane- spanning segments in proteins. The program is now available on the worldwide web at http://www.bioinformatics-canada.org/TM/

Dr. Zongchao Jia (Queen's University) - the Premier Research Excellence Award, from the Ontario Government and the Basmajian Award for Excellence in Medical Research, Queen's University.

Dr. Claude Lazure (Institut de Recherches Cliniques de Montréal (IRCM)) - was an invited member at the BMA Committee of the ex-MRC (now CIHR) (2000) and was also an internal reviewer at the FRSQ (Senior fellowships) in 2000.

Dr. Ron McElhaney (University of Alberta) - has been selected to receive the Avanti Award in Lipids from the Biophysical Society for Excellence in lipid and membrane research.

Dr. Lawrence McIntosh (University of British Columbia) - the Alexander von Humbolt Fellowship (1999) and the CIHR Scientist (2000).

Dr. Tony Pawson (Mount Sinai Hospital) - the J. Allyn Taylor International Award in Medicine (2000), the Killam Prize in Medicine (2000) and was made an Officer of the Order of Canada (2000).

Dr. Harry Schachter (Hospital for Sick Children and University of Toronto) - 2000, organized the Second International Symposium on Glycosyltransferases, Hospital for Sick Children.

Dr. John Schrader (University of British Columbia) - the Cinader Award, Canadian Society for Immunology, Canada (1999) and the UBC Killam Award, University of British Columbia, Canada (2000).

Dr. Nabil Seidah - Institut de Recherches Cliniques de Montreal (IRCM) - 1999 received the PMAC Health Research Foundation Medal of Honor (now Canada's Research-based Pharmaceutical Companies, Rx&D).

Dr. Brian Sykes (University of Alberta) was appointed Fellow of the Royal Society of London (FRS) in July 2000, and Appointed Chair of the Biochemistry Department, July 1999. He is also head of NANUC (National High Field Nuclear Magnetic Resonance Centre) - Western Canada's first and only 800 MHz Nuclear Magnetic Resonance Facility.

Dr. David Wishart (University of Alberta) is the CIHR-Rx&D Research Chair (2000-2005).

18 2000 ANNUAL REPORT CELEBRATING OUR SCIENTIFIC EXCELLENCE

Post-Doctoral & Graduate Students (Supervising Principal Investigator is shown in parentheses)

Sarah Everts, University of British Columbia (Dr. Lawrence McIntosh) - NSERC PGS-B (Declined).

Dr. Steffen Graether, University of Alberta (Dr. Brian Sykes) - AHFMR Fellowship; CIHR Research Allowance.

Chris Hosfield, Queen's University (Dr. Zongchao Jia ) - MRC (now CIHR) doctoral studentship.

Dr. Robert Ingham, Mount Sinai Hospital (Dr. Tony Pawson) - NCIC Fellowship.

Dr. David Keizer, University of Alberta (Dr. Brian Sykes) - AHFMR Travel Award.

Dr. Christoph Mayer, University of British Columbia (Dr. Steve Withers) - Swiss National Science Foundation Fellowship.

Dr. Siew Hwa Ong, Mount Sinai Hospital (Dr. Tony Pawson) - NMRC - Singapore Totalisator Board Medical Research Scientist Award. Protein

Dr. Pamela Plant, Mount Sinai Hospital (Dr. Tony Pawson) - CIHR Fellowship. discoveries Dr. Nadia Rabah, Institut de Recherches Cliniques de Montréal (Dr. Claude Lazure) - Awarded an FCAR-FRSQ studentship and an award from McGill Division of Experimental Medicine for academic performance. for the new

Dr. Johann Schloegl, University of British Columbia (Dr. Steve Withers) - Erwin Schroedinger Fellowship, Austria. millennium

Dr. Robert Steven, Mount Sinai Hospital (Dr. Tony Pawson) - CIHR Fellowship.

Dr. Chris Tarling, University of British Columbia (Dr. Steve Withers) - Royal Society (UK) Post-doctoral Fellowship.

Gary Van Domselaar, University of Alberta (Dr. David Wishart) - Rx&D HRF Graduate Student Fellowship (2000-2002).

David Vocadlo, University of British Columbia (Dr. Steve Withers) - NSERC Graduate Studentship.

Dr. Spencer Williams, University of British Columbia (Dr. Steve Withers) - Killam Post- doctoral Fellowship.

David Zechel, University of British Columbia (Dr. Steve Withers) - Killam Graduate Studentship; University Graduate Fellowship.

19 EXTRACTS FROM FINANCIAL STATEMENTS

PENCE Inc. Extracts from Financial Statements For the year ended March 31

STATEMENT OF OPERATIONS AND UNRESTRICTED NET ASSETS

2000 1999 REVENUE Contributions $ 5,919,645 $ 7,916,596 Royalties and other income 78,591 10,695 5,998,236 7,927,291 EXPENSES Research programs 4,308,892 5,446,861 Core facilities 341,362 263,239 Capital equipment grants to members 423,069 1,618,619 Networking programs 127,313 73,335 National and regional operating expenses 912,717 595,808 6,113,353 7,997,862 Deficiency of revenue over expense for the year (115,117) (70,571) Unrestricted net assets, beginning of year 369,861 440,432 Unrestricted net assets, end of year $ 254,744 $ 369,861

STATEMENT OF FINANCIAL POSITION

ASSETS Current Cash $ 14,564 $ 14,358 Amounts held by member institutions [note 3] 2,357,450 1,486,723 Contributions receivable 123,400 135,175 2,495,414 1,636,256 LIABILITIES AND NET ASSETS Current Amounts payable 155,688 21,881 Deferred contributions [note 4] 2,084,982 1,244,514 2,240,670 1,266,395 Net assets Unrestricted net assets 254,744 369,861 $ 2,495,414 $ 1,636,256

Note 3. The amounts held by member institutions represents the balance of NCE grants and other funds held on behalf of PENCE as at the end of the year.

Note 4. Deferred contributions represent NCE and other grant funds which were externally restricted for expenditure on specific research projects or for capital equipment but not utilized as of the end of the year.

PENCE receives the majority of its funding from the Natural Sciences and Engineering Research Council ("NSERC") and the Medical Research Council (Canadian Institute for Health Research) under the NCE program. Future funding under the program is expected to be $4,500,000 per year until March 31, 2002, subject to annual availability of funds. PENCE's ability to maintain viable operations is dependent upon continued support under the NCE program.

The value of in-kind contributions of goods and services are not reflected in these financial statements. Complete audited financial statements are available on request.

20 2000 ANNUAL REPORT THE PENCE NETWORK STRATEGIC PARTNERS

* Signatories to the PENCE Inc. Phase III Network Agreement

Universities* McGill University Queen's University Simon Fraser University Université de Montréal University of Alberta University of British Columbia University of Calgary University of Guelph University of Toronto University of Victoria University of Waterloo University of Western Ontario

Research Institutes and Hospitals* Biotechnology Research Institute Hospital for Sick Children Institut de Recherches Cliniques de Montréal Loeb Health Research Institute (University of Ottawa, Ottawa Hospital) Mt. Sinai Hospital Ontario Cancer Institute/Princess Margaret Hospital

Federal Agencies* Natural Sciences and Engineering Research Council of Canada Protein Medical Research Council (Canadian Institute for Health Research)

Other Alberta Peptide Institute discoveries Alberta Research Council Alberta Science & Research Authority Blake, Cassels & Graydon for the new British Columbia Science Council Canadian Bacterial Diseases Network Canadian Genetic Diseases Network Canadian Foundation of Innovation millennium Centre de Recherché en Calcul Appliqué (CERCA) Founders' Network Iota Pi Law Group Japanese Society for the Promotion of Science Killam Foundation Ontario Innovation Fund PAPRICAN Province of Ontario Samuel Lunenfeld Research Institute Swiss National Science Foundation

Industry A/F Protein Inc. AltaRex Inc. AstraZeneca Bayer Biological Products BioTools Inc. Biomira Inc. Cangene Corporation CBD Technologies Inc. Converzyme Inc. Cytovax Biotechnologies Inc. Glaxo Wellcome Inc. GLYCODesign Inc. Helix BioPharma Corp. Hoechst Marion Roussel IBIS Pharmaceuticals Inc. Iogen Corp. Merck Frosst Canada Inc. Micrologix Biotech Inc. NEOSE Technologies Inc. Novartis Pharmaceuticals Inc. Novo Nordisk Inc. Osprey Pharmaceuticals Inc. Pasteur Mérieux Connaught Ltd. Sensium Technologies Inc. Warner-Lambert Canada Inc.

21 THE PENCE NETWORK RESEARCHERS & ADMINISTRATION

PENCE Network Investigators PENCE BOARD OF DIRECTORS Dr. D. Argyropoulos, McGill University 1999-2000 Dr. E. Ball, University of Western Ontario Dr. J.F. Mustard, Chair, Founders' Network Dr. G. Brayer, University of British Columbia Ms. B. Brennan, PhilomBios Dr. D. Bundle, University of Alberta Dr. M. Chrétien, Loeb Health Research Institute Dr. M. Chrétien, Loeb Health Research Institute Dr. R.B. Church, University of Calgary Dr. I. Clark-Lewis, University of British Columbia Dr. R. Fraser, University of Alberta Dr. M. Cygler, Biotechnology Research Institute Mr. B.W. Gray, Blake, Cassels & Graydon Dr. P. Davies, Queen's University Ms. N. Harrison, Ventures West Management Inc. Dr. J. Elce, Queen's University Dr. R.S. Hodges, University of Alberta Dr. S. Fortier, Queen's University Dr. J. Levy, QLT Phototherapeutics Inc. Dr. J. Gariépy, University of Toronto Dr. M. Piper, University of British Columbia Dr. J. Glasgow, Queen's University Dr. S. Withers, University of British Columbia Dr. M. Glover, University of Alberta Dr. C. Yip, University of Toronto Dr. J. Gunn, Université de Montréal Dr. G. Macaloney, PENCE National Business Centre Dr. C. Haynes, University of British Columbia (ex-officio - non-voting) Dr. R. Hill, Ontario Cancer Institute Ms. L. Mealing, NSERC (non-voting observer) Dr. O. Hindsgaul, University of Alberta Dr. R. Hodges, University of Alberta Dr. Z. Huang, Merck Frosst Canada Inc. INTERNATIONAL RESEARCH Dr. R. Irvin, University of Alberta ADVISORY COMMITTEE Dr. Z. Jia, Queen's University 1999-2000 Dr. C. Kay, University of Alberta Dr. C. Kay, Chair, University of Alberta (Canada) Dr. L. Kay, University of Toronto Dr. M. Chrétien, Loeb Research (Canada) Dr. D. Kilburn, University of British Columbia Dr. C. Dobson, (United Kingdom) Dr. R. Kluger, University of Toronto Dr. K. Drickamer, University of Oxford (United Kingdom) Dr. G. Krepinsky, University of Toronto Dr. J. Greenblatt, University of Toronto (Canada) Dr. C. Lazure, Institut de Recherches Cliniques de Montréal Dr. R. Hodges, University of Alberta (Canada) Dr. D. Leech, Université de Montréal Dr. H. Schachman, University of California, Berkeley (United States) Dr. B. Lennox, McGill University Dr. M. Smith, University of British Columbia (Canada) Dr. F. Major, Université de Montréal Dr. A.G. Mauk, University of British Columbia MANAGEMENT AND SCIENTIFIC Dr. R. McElhaney, University of Alberta Dr. L. McIntosh, University of British Columbia PLANNING COMMITTEE Dr. R. Ménard, Biotechnology Research Institute/McGill 1999-2000 Dr. J. Mort, McGill University Dr. R. Hodges, Chair, University of Alberta (June 2000) Dr. F. Ni, Biotechnology Research Institute/McGill Dr. S. Withers, Chair, University of British Columbia (July 2000) Dr. M. O'Connor-McCourt, Biotechnology Research Institute/McGill Dr. D. Bundle, University of Alberta Dr. F.P. Ottensmeyer, Ontario Cancer Institute Dr. Z. Huang, Merck Frosst Canada Inc. Dr. E. Pai, University of Toronto Dr. R. Irvin, University of Alberta Dr. M. Paice, Pulp & Paper Research Institute of Canada Dr. L. Kay, University of Toronto Dr. A. Pawson, Mt. Sinai Hospital Dr. D. Rose, Ontario Cancer Institute Dr. M. Pinto, Simon Fraser University Dr. H. Schachter, Hospital for Sick Children, Toronto Dr. E. Purisima, Biotechnology Research Institute/McGill Dr. J. Schrader, University of British Columbia Dr. J. Rini, University of Toronto Dr. D. Segal, Helix BioPharma Corp. Dr. D. Rose, Ontario Cancer Institute Dr. A. Storer, Biotechnology Research Institute, Montréal Dr. B. Roux, Université de Montréal Dr. R.A.J. Warren, University of British Columbia Dr. J. Saddler, University of British Columbia Dr. G. Macaloney, PENCE Inc. (ex officio - non-voting) Dr. U. Saragovi, McGill University Mr. R. Joseph, PENCE Inc. (ex officio - non-voting) Dr. H. Schachter, Hospital for Sick Children Ms. L. Mealing, PENCE Inc. (Non-voting observer) Dr. J. Schrader, University of British Columbia Dr. N.G. Seidah, Institut de Recherches Cliniques de Montréal NATIONAL Business Centre Dr. A. Storer, Biotechnology Research Institute 1999-2000 Dr. B. Sykes, University of Alberta Dr. R. Hodges, CEO / Scientific Director (June 2000) Dr. M. Tyers, Mt. Sinai Hospital Dr. S. Withers, CEO / Scientific Director (July 2000) Dr. C. Upton, University of Victoria Dr. G. Macaloney, COO Dr. A. Vrielink, McGill University Ms. T. Campbell, Manager, Dr. R.A.J. Warren, University of British Columbia Marketing & Communications/Project Coordinator Dr. D. Wishart, University of Alberta Mr. R. Joseph, Manager, Business Development Dr. S. Withers, University of British Columbia Ms. D. Wilchak, Coordinator, Finance & Administration Dr. H. Ziltener, University of British Columbia Ms. E. Poirier, Network Secretary Mr. I. Dijkstra, Business Development - MBA Intern PENCE Industry Investigators Mr. D. Lesoway, Marketing & Communications - MBA Intern Dr. J. Carver, GLYCODesign Inc. Mr. D. Lo, Business Development - MBA Intern Dr. J. Dennis, GLYCODesign Inc. Ms. R. Yakimchuk, Finance & Administration Assistant (part-time) Dr. D. Segal, Helix BioPharma Corp.

Affiliated Network Investigators PENCE Regional Centre Directors Dr. Y. Aubin, Merck Frosst Canada Inc. 1999-2000 Dr. C. Deber, Hospital for Sick Children Dr. A.G. Mauk, British Columbia Dr. L. Howell, Hospital for Sick Children Dr. E. Pai, Ontario (Co-Director) Dr. G. Lajoie, University of Waterloo Dr. H. Schachter, Ontario (Co-Director) Dr. H. Lee, University of Guelph Dr. J. Mort, Quebec Dr. G. Privé, Ontario Cancer Institute Dr. B. Sykes, Alberta Dr. B. Sarkar, Hospital for Sick Children Dr. J. Trevors, University of Guelph Dr. H. Vogel, University of Calgary 22 2000 ANNUAL REPORT