Emerging Era of Very safe and Novel Therapeutics with Humanized Recombinant Antibodies Produced in Plants : Mr G.P. Talwar, Talwar Research Foundation, New Delhi

My presentation would consist of

1) Introduction of antibodies as highly safe therapeutic drugs,

2) Scope to replace horse derived antibodies for life threatening situations by Humanized Recombinant
Antibodies (HRA) .

3) Two HRA-chimeric antibodies generated; their applications for Emergency contraception, Vacation
Contraceptive (Home Leave), Prostate enlargement and cancers

4} Exquisite capacity of Plants to produce Recombinant Antibodies.

Introduction - Unique Properties of antibodies

Antibodies have exquisite specificity to bind selectively with a target antigen without interference from a multitude of others present in the medium. It is this property which forms the basis of their use in diagnosis. A revolution has occurred in devising of a large number of highly sensitive and discriminating enzyme immunoassay kits employing monoclonal antibodies, which enable the detection and quantitation of ligands present in pico to nanogram quantities in blood and other specimens without necessity of their separation or purification from hundreds of others present in the fluid. The production of monoclonal antibodies on industrial scale was ushered by the innovative work of Nobel prize winners Kohler and Milestein within a decade, which is an example of fruitful Academia-lndustry interaction. Monoclonal antibodies are products of hybridoma cells created by the fusion of an antibody forming cell with a cell with perpetual ability to multiply. The hybrid cell inherits the dual properties of multiplying without limit and making only one type of antibody. Thus monoclonal antibodies are homogenous and have consistent characteristics of binding affinity and specificity for a given antigen, traits that are useful for an industrial product.

Given this selective capability of antibodies to react with a given target molecule and not cross-react with others, they could constitute highly safe agents for therapeutic intervention. Rare are the drugs developed by the pharmacological route, which donot have some side effects, eventhough minor, and these are selected for treatment on basis of relative benefit versus hazard. Therapy with monoclonal antibodies would be focus only on a given target and spare the rest, minimizing if not eliminating totally the side effects. These would therefore, be the safest "drugs" of the future.

Life saving serotherapies

Antibodies have been used since the past many years for therapeutic purposes. Their use has infact been made in life saving situations for treatment of advanced cases of tetanus, diptheria and rabies where vaccines could be of no avail, as vaccines take time to generate antibodies and what is needed at the advanced stage of disease is immediate intervention. Serotherapy or the passive use of antibodies for these infections employed antisera raised in horses. The horse derived antibodies, though effective for the purpose, cause sensitization of the recepient to the species proteins, with the result that repeated use of such antibodies can not be made in the same individual. In more recent years, immunoglobulins prepared from the serum of humans who undergo hyper-immunization with the corresponding vaccines have become available commercially. These do not have the above stated drawback, although they are expensive. Horse derived antisera continue to be the vital life saving therapy against snake bites.

Thus therapy by antibodies directed at toxins or venom constituents has been practiced in humans since many decades and has largely proven its value and utility. The extension of this principle to other target molecules can be done with expected advantages. Horse has to be abandoned as source of antibodies. Deriving immunoglobulins from hyper-immunized humans is not cheap nor feasible for all antigens. Furthermore there are variations from individual to individual with respect to the class, specificity and spectrum of antibodies made by them in response to the same antigen. Consistency of antibody characteristics can be assured by recourse to monoclonal antibodies. Technology is freely available and employed widely to generate monoclonal antibodies in mice.

Humanization of mouse monoclonals

Technologies for humanization of mouse monoclonals have recently been developed. The pathway to do so is briefly as follows: The genes coding for the variable part of light (VL) and heavy (VH) chains of the chosen antibody are identified and cloned from the transcript of mouse hybrid cells engaged in making only the chosen monoclonal antibody of the desired characteristics. The sequence of bases in the complementarity determining regions (CDRs) provides the signature of elements for binding with the putative antigen. Thereafter the VH and the VL can be engineered in various formats: as a signle chain variable fragment containing both VH & VL (ScFv), as a diabody or as a chimeric antibody, in which the mouse variable chains are fused with the human light and heavy constant domains. In either case, the next logical step is to produce the antibody by DMA recombinant methods in either bacteria, yeast or plants. While chimeric antibodies have been approved by US FDA and other International Drug Regulatory Authorities for clinical trials in cancers, allergies, reheumatic arthritis etc, further humanization of chimeric antibody can be done by replacement of the mouse frame work residues in the variable chains by human analog amino acids.

We will now describe two chimeric recombinant antibodies that we have been successful to make and express with high yield in plants.

Recombinant chimeric antibody against the human chorionic gonadotropin (hCG), its applications for Emergency Contraception, Vacation Contraceptive and Cancers

HCG is an oncofoetal protein made soon after conception and has a critical role in implantation of the embryo onto the womb. Antibodies inactivating hCG block the onset of pregnancy as well as its sustenance over the first 7 weeks. Thus these can be used for

(a) Emergency contraception to prevent the onset of pregnancy with the advantage of use upto 6-9 days after
unprotected sex, whereas the Yuzpes regime is effective only upto 48-72 hours

(b) Menstrual regulation (inducing delayed menstruation) or as

(c) Home Leave, Vacation Contraceptive, providing protection from an unwanted pregnancy for 4-6 weeks after a single injection without disturbance of ovulation, spotting, bleeding irregularities or mood change.

During my tenure of Jawaharlal Nehru Fellowship (JLN) , we had developed a mouse monoclonal antibody (MoAb) against hCG. This MoAb has highly meritorious characteristics. It has a high affinity for binding with hCG (Ka=1010 M-1), and is totally devoid of reactivity with pituitatry hormones, hFSH and hTSH and has less than 5% cross-reactivity with hLH. It is bioeffective and neutralizes the activity of hCG in both invitro and invivo systems. The rights to this clone were given to me as per the rules of the JLN Fellowship. This antibody was solicited by M/s Carter Wallace Wampole Laboratories USA for use in internationally marketed Pregnancy Diagnosis kits. It is this antibody (PIPP) which was taken up for "humanization". It has been engineered into a chimeric antibody in which the constant regions are human IgG1 and human kappa. The recombinant antibody retains the high affinity of the parent PIPP, Ka =1010 M-1 , with the same discriminatory specificity. It is bioeffective to inhibit the hCG induced production of testosterone by the Leydig cells. It is also effective in blocking the hCG induced increase of uterine weight of immature mice.

This antibody has been transiently expressed in tobacco leaves. The yield of the purified antibody is 20 -24 mg per kg of fresh leaves of tobacco. Probing experiments have shown that several non tobacco plants such as spinach, zuchini, aubergines can also make this antibody.

The potential utility of this highly cost effective antibody is in the following applications based on the dual nature of hCG as an oncofoetal protein. It is produced by the early embryo and also by many cancers, specially when they become aggressive (metastasis).

1) Use as a key ingredient in immunodiagnostic kits for pregnancy. Plant produced humanized antibodies
may be more economical in kits which are used in very large numbers.

2) Cancers : Diagnosis, prognosis and determination of complete surgical removal of tumours making hCG
(30 different cancers are reported to make hCG). Detection of reappearance of metastasis and for evaluation
of efficacy or otherwise of chemotheraphy and radiations.

3) As several tumours making hCG have receptors for this hormone on ' membranes, radio-labeled high affinity
antibodies can be used for imaging of metastasis of the tumour and as vehicle for focused delivery of
radiations to the tumour.

4) Selective delivery of drugs to tumours lessening their systemic toxicity. Immunotoxins where a toxin or drug
is loaded on the antibody are being made for cancer therapy.

5) Emergency Contraception : Interception of implantation by anti hCG antibodies to ward off an unwanted pregnancy following unprotected sex, rape or incest. Advantage over presently marketed Yuzpes regime of steroid hormones is a much wider time window for intervention (6-9 days Vs 2-3 days) and lack of side effects like nausea, vomiting.

6) Menstrual Regulation to induce delayed menstruation (non surgical early abortion)

7) Home Leave/Vacation Contraception offering protection to women from becoming pregnant for 4-6 weeks (or longer depending on dose) after a single intake of immunoglobulins. Antibodies do not impair ovulation nor cause amennorrhea, spotting or bleeding irregularities, which are the accompanying actions of injectible steroids.

An advantage of passive immunotherapy is in assuring efficacy in every recepient. Performed antibodies at the desired dose are delivered as drugs. This overcomes the uncertainty of antibody response to a vaccine as all individuals do not respond positively to immunization with a vaccine. Furthermore the titres of antibodies vary from individual to individual. The duration of immune response is also variable. These unpredictabilities are taken care of by using preformed antibodies of tested efficacy.

Recombinant chimeric antibody against LHRH

LHRH is a decapeptide made in the hypothalamus. It is a master molecule. It controls the secretion of pituitary gonadotropins and thereby the generation of gametes (sperm in male, egg in female) and also production of sex steroid hormones (testosterone in males, estrogens, progesterone in females). LHRH is identical in males and females (a unisex molecule). Furthermore it is conserved during evolution and has essentially the same structure in all mammals (rodents, dogs, pig, humans) Antibodies reactive with LHRH have the following useful applications :

In animals

a) Control of estrus of companion animals, dogs and cats

b) Improvement of the quality of meat from male pigs, goats, rams.

Prostate hypertrophy and carcinoma of prostate

We have demonstrated previously that a semisynthetic vaccine made against LHRH causes atrophy of the prostate. The vaccine underwent preclinical toxicology and Phase I/Phase II clinical trials in 28 advanced stage prostate carcinoma patients at AIIMS- (All India Institute of Medical Sciences) New Delhi, PGI- (Postgraduate Institute of Medical Education and Research) Chandigarh & Urology clinic at Salzburg (Austria).

The vaccine was found safe with no side effects ascribable to immunization. 400 mg dose was more immunogenic than 200 mg. Patients with antibody titres above 400 pg/ml experienced clinical well being with decline in PSA (Prostate specific Antigen) and acid phosphatas. The vaccine has potential utility in benign prostatic hypertrophy, specially in those cases where surgery is not indicated due to medical reasons. It is also effective in prostate cancers upto the stage that they are androgen dependent. We have created recently a DMA recombinant vaccine easier and cheaper to make on industrial scale. The new vaccine would also be eligible for world wide patenting.

The recombinant chimeric antibodies are complementary products to the vaccine. These exercise efficacy soon after delivery whereas the vaccines have a latent period of 4-8 weeks for building up the antibody titres.

A monoclonal for androgen independent carcinoma of prostate

We have developed a unique monoclonal antibody which is cytotoxic to human androgen independent prostate carcinoma cells ( Talwar et al , 2001. The Prostate 43: 207-213). At present no effective chemotherapy is available for this stage of prostate cancers, which leads eventually to death of patient. The antibody has no immunopathological reactivity to other normal human tissues.

Plants as ecofriendly source of Recombinant Antibodies

It is amazing that plants express the engineered genes of antibodies quite faithfully. Normally antibodies are animal products. Both the light and heavy chains of the imunoglubulin are made correctly with S-S linkage within the chain and in the intra chains put in the right place to generate functional antibodies. The yield of the chimeric anti hCG antibody during transient expression ranged from 20-24 mg of pure antibody per Kg fresh weight of leaves. The purification was achieved in a single step by affinity chormotography on protein A/G column. From safety point of view, plant products may be safer as these are less likely to pass on viruses pathogenic to humans.

BIOTECHNOLOGY POLICY 2001 ANDHRA PRADESH

"Biotechnology is a frontier technology which has the potential to provide benefits in several ways to all sections of the society, but more so to the very poor by facilitating the manufacture of cheaper, safer and more effective drugs, improving the quality of livestock, agriculture and improving the quality of life."

N.Chandrababu Naidu
Chief Minister of Andhra Pradesh

Andhra Pradesh - the competitive edge

Rich bio-resources

• 7 agro-climatic zones
  
• 19 major food and commercial crops
  
• More than 5000 species of trees, of which 2000 are flowering trees
  
• 40% land in agricultural use
  
• 23% land under forest cover
  
• 974 kms coastline
  
• Leading producer of cash crops

  ....abundant and diverse agriculture and forest wealth

A leader in pharmaceuticals - medical & health care

• The bulk drug capital of India
  
• Internationally renowned for chemical synthesis and process engineering
  
• Invention of new molecules
  
• Premier health care institutions
  
  ....unique advantage in the field of pharma biotech
  

Agri State

• Rice Bowl of South India
  
• Poultry Capital of India
  
• Seed State of the Country
  
• Ranking in production:
  
  • First in Mango, Turmeric, Citrus, Papaya, Tobacco, Maize, etc.
    
  • Second in Fresh Water Fisheries, Sericulture, Sheep, etc.
    

A network of R&D Infrastructure

• Centre for Cellular and Molecular Biology
  
• Centre for DNA Fingerprinting and Diagnostics
  
• Indian Institute for Chemical Technology
  
• International Crop Research Institute in Arid and Semi-Arid Tropics (ICRISAT)
  
• Directorate of Rice Research
  
• National Institute of Nutrition
  
• Dr. Reddy's Research Foundation
  
• Hyderabad Eye Research Foundation
  
• Institute of Genetics
  
• Directorate of Oil Seed Research
  
• National Research Centre for Sorghum
  
• Central Research Institute for Dry Land Agriculture
  
• NIIMS, SVIMS, NTRHU....
  ....unique advantage in R&D

Centres of excellence in Biotechnology

• Centre for Cellular and Molecular Biology
  
• Centre for DNA Fingerprinting and Diagnostics
  
• National Institute of Nutrition
  
• Laboratory for the Conservation of Endar Species
  
• Directorate of Rice Research
  ....provides base for modern biotechnology

Availability of scientific & technical manpower

• University of Hyderabad
  
• Osmania University
  
• Jawaharlal Nehru Technological University
  
• Acharya NG Ranga Agricultural University
  
• Kakatiya University
  
• Nagarjuna University
  
• Andhra University
  
• Sri Venkateswara University
  
• Sri Krishna Devaraya University
  
• Sri Padmavati Mahila Visvavidyalayam
  ....large pool of scientific & technical manpower
  

Leading Biotech Companies

• Shanta Biotechnics
  
• Bharat Biotech
  
• Dr. Reddy's Labs
  
• Jupiter Bio Science
  
• GVK Biosciences
  
• Fortune Biotech
  
• Pro Agro
  
• Nagarjuna Biotech
  
• Krebs Biotech
  
• Micro Biomed
  ...existence of a critical mass for the Biotech industry

Evolution of Biotech Policy

• Biotechnology Advisory Committee set up
  
• Dr Manju Sharma, Secretary, DBT, as patron
  
• Members:
  
  • Eminent biotechnologists-
    
    • Dr. D Balasubramanian
      
    • Dr M V Rao
      
    • Dr A Venkateswarlu
      
    • Dr. Lalji Singh
      
    • Dr. Seyed Hasnain
      
  • Secretary Industries & Commerce
    
  • Representative - JV Company for Biotech Park
    
  • Representative - Ernst & Young
    
  • Consultations with entrepreneurs, academia, Government and scientists for feedback/suggestions
    

Objectives of the Policy

• Inventory of the bio-resources of the State
  
• Conservaton of Bio-diversity & sustainable exploitation of bio-resources
  
• Encouragement of R&D through infrastructure development
  
• Setting up of state-of-the-art Biotech parks
  
• Special incentives to the Biotech industry
  

Objectives of the Policy...

• Leveraging IT strengths for Bioinformatics
  
• Focus on Human Resource Development
  
• Create enabling environment
  
• Facilitate flow of venture capital funds and bank credit
  
• Address IPR, bio-ethics and bio-safety issues
  

Thrust Areas

• Diagnostics
  
• Therapeutics
  
• Pharmacogenomics
  
• Bioinformatics
  
• Agriculture Biotechnology
  
• Industrial Biotechnology
  
• Inputs to the Industry
  
• Marine Biotechnology
  
• Forest and Environment focused Biotechnology
  
• Contract Research
  

Encouraging R&D

• ICICI Knowledge Park to provide:
  
  • Ready to use modules
    
  • Lands for setting up units also available
    
• Encourage Universities to undertake Contract Research
  
• Leveraging availability of good quality man-power
  
• Facilitating MNCs to set-up R&D units
  

Biotech Infrastructure

• Good quality infrastructure at reasonable cost
  
• Integrated services
  
• Proposed Initiatives
  
• Biotech Park in Turkapally, Hyderabad
  
• Park will house a National Resource Centre
  
• Biotech Parks at other places
  
• Biotech Industry would be exempt from Power Cuts
  
• Genome Valley encompassing Shamirpet, Medchal, Keesra, and Uppal - 600 sq kms
  

Biotech Park, Turkapally

• The project is proposed to be developed in an area of 300 acres and located near ICICI Knowledge park
  
• Novel Concept and first of its kind in the country
  
• Will provide all the necessary infrastructure and suitable environment for the development of the sector
  
• Aims to focus at Bio-Pharma, Health Care, & Agri companies in the first phase
  
• Will act as a catalyst to attract the biotech industry to the State
  
• The project shall be supported in the form of grants, subsidies, sales tax concession, soft loans etc. (from domestic and overseas agencies)
  
• Basic Infrastructure like Telecommunication facilities, Power, and the like are already available near the park
  
• The proposed park will have state-of-the-art communication facilities, utilities, potable water, de-ionised water, roads and treatment plants
  

Advantage Biotech Park

The Biotech Park will provide following READY benefits to the tenants:

• World Class Infrastructure
  
• Service providers
  
• Ready-to-occupy flatted factories
  
• Security
  
• Residential complex in close proximity
  
• National Resource Centre (to be set up by Dept of Biotechnology)
  
• Sales Tax Incentives
  
• Single Window Clearance
  
• Instant Customs Clearance
  
• Provide "Idea to Commercialisation"
  
• Thrust in one or few areas of prioritised industry segments
  
• Networking between research and academic institutions
  
• Reduces the capital outlay for entrepreneurs
  
• Improved rate of return on investment
  

Incentives

• Sales Tax Incentives - 1% (as against the existing 8-16%)
  
• Land for Biotech Parks/Activities
  
• Bioinformatics:
  
  • Concessional Lands:
    
    • Rs 30,000 per job created in the Genome Valley
      
    • Rs 20,000 per job created at other locations
      
  • 100% exemption from Registration & Stamp Duty
    
• Land in Genome Valley for training institutes
  
• Land for Housing in Genome Valley for Biotech personnel
  
• Special incentives for Mega projects
  

Labour Concessions

• General Permission to run three shifts
  
• Permission for women to work in third shift
  
• System of self certification to be permitted to Biotech units
  
• Amendment of A.P. Shops and Establishment Act
  
• Exemptions from the provisions of Contract Labour Act 1970
  
• Delegation of powers of labour commissioners
  
• Special Industrial Tribunal for the Biotech Parks
  

HR Initiatives

• Undergraduate and graduate courses in Biotechnology introduced in universities
  
• Universities would be granted one time grants for setting up infrastructure for R&D in the area of Biotechnology
  
• Enable collaborations with universities and biotech labs across the world
  
• ASCI will launch several short term courses in Bioinformatics and management of Biotech companies
  
• National Resource Centre would organise various seminars and workshops
  
• Institute of Bioinformatics and Applied Biotechnology (IBAB) would be set up in the ICICI
• K-Park on the lines of CNRS, France/Howard Hughes Foundation, US - a "virtual" institute
  

Venture Capital Support

• APIDC Venture Capital Limited will facilitate funding of Biotech startups
  
• Government would set-up a Biotechnology Development Fund with an initial corpus of Rs 50 crores
  
• Efforts to attract leading Venture Capitalists
  

Creating an enabling Environment

• Andhra Pradesh Biotechnology Development Council, under the Chairmanship of the Chief Minister
  
• Department of Biotechnology
  
• Biotechnology Advisory Committee
  

"Enabling Mechanisms for Biotechnology - Initiatives by State Governments" M.R. Das, RGCB, Trivandrum, Kerala

In presenting the "Mechanisms for Biotechnology - Initiatives by State Governments", I am essentially limiting the experience in the State of Kerala. There are two reasons for doing this. The first has to do with the fact that Kerala already had a good infrastructure and seven vibrant laboratories are under the State Department of Science & Technology. This was a consequence of the farsightedness of our late Chief Minister, Shri Achutha Menon who took the initiative in establishing these research centres in different parts of Kerala. His vision was to develop the laboratories on the same line as Central Laboratories with a view not only to solve problems of local interest but also to address basic problems at the cutting edge of Science. Among the laboratories that were started in the Seventies are the Kerala Forest Research institute (KFRI), Peechi, Tropical Botanic Garden & Research Institute (TBGRI), Trivandrum, Centre for Water Resources Development & Management (CWRDM), Kozhikode, Agency for Non Conventional Energy and Rural Technology (ANERT), Trivandrum and National Transportation Planning and Research Centre (NATPAC), Trivandrum. For this reason for starting an advanced centre for plant biotechnology, there was excellent infrastructure already available. The contributions of these laboratories are unfortunately more well known outside of India rather than within India, for the simple reason that they are not under any of the central agencies like DBT, DST, CSIR or DAE.

The second factor was the establishment of the seventh laboratory under the State Government, the Rajiv Gandhi Centre for Biotechnology in Trivandrum in early 1995. This was established primarily at the instance of Dr. P.K Iyengar, former Chairman, Atomic Energy Commission and Secretary, Department of Atomic Energy, while he was in Kerala for a short while as Chairman, Science and Technology Dept., Govt. of Kerala. Soon after he took over the Chairmanship of Science and Technology, Govt of Kerala, he contacted me and asked me whether we could develop a state of the art laboratory with international standards on a futuristic subject, like Biotechnology. I had accepted the challenge and moved to Trivandrum from CCMB, Hyderabad in 1995. In planning laboratory activities, policy decisions were made such that the organisation of the laboratory will be similar to that of the Max Plank institutes of Germany or TIFR or CCMB, that is to say, the Centre will not have any departmental structure as in the Universities, but we will have research groups under group leaders of proven track records in terms of publications, awards, fellowship of scientific academies and the like. As we were starting from scratch, to start with, two more senior scientists were recruited and the three of us planned for necessary equipments and chemicals and procured them before further recruitment of scientists. This was primarily for the reason that newly appointed scientists should have much shorter lag time after joining the Centre. Otherwise, each should have had to wait for longer periods to time to have all the equipments and chemicals available for starting the work.

From day one, this idea was discussed with the Department of Biotechnology with both Dr. S. Ramachandran and Dr. (Mrs.) Manju Sharma along with Dr. Iyengar. The discussions were extremely fruitful and the DBT decided to support the establishment of the new institution entirely devoted to Biotechnology handsomely. All the recruitments were carried out by a national committee consisting of very eminent scientists in the area of modern life sciences. Once the group leaders were recruited, other junior level scientists and research fellow (both JRF and SRF) and research associates were appointed. Briefly, in a short while, we have been able to establish credibility through publications in prestigeous International and national journals. Our annual reports and publication records stand testimony for this. We have also been fortunate to attract two Nobel Prize winning Scientists, such as Prof. James Watson and Prof. Harold Varmus to visit us and give lectures while they were visiting India.

The presentation would also include the experience in the development of Biotechnology at the State level with positive interactions with the Chief Ministers who were and are extremely supportive of the development of Biotechnology.

Ten Years Ahead:Clinical Trials in the Genomic Era 15th National Conference on in-house R&D in Industry FICCI Golden Jubilee Auditorium New Delhi November 22-23, 2001 Oppel Greeff, MBChB, MFGP (SA), MPharmMed, FFPM (RCP), MD President - CPO : Africa-Indian and Latin American Regions Quintiles

Abstract

The field of medicine is exploding with ideas, and we are surrounded by great opportunity as industry rushes to implement them. The map of the human genome completed in 2000 is a turning point in biomedical history. It opens vast new possibilities to understand our own life processes and to combat disease. I would like to tell you how I see this new medicine evolving in the next decade, and how India's emerging pharmaceutical industry can play a role in creating the medicine of the 21st century.

The new medicine will be built on a combination of biotechnology and information technology. Progress in biotechnology will create individualized therapy that is based increasingly on a patient's genetic profile. Today's "one-size-fits-all" medicine will seem primitive by comparison. These new therapies will emerge from advances human genome mapping, in gene function discovery and in proteomics, the study of gene-governed proteins. Progress in information technology will help generate these advances and deliver their benefits worldwide.

The clinical trial will be at the heart of implementing this new medicine, and global clinical research will be vital to study new therapies in all populations of the world. Clinical research organisations (CROs) will make significant contributions to this effort. They provide medical and scientific expertise, information technology to manage the great mass of data generated by clinical trials, and capabilities to conduct clinical research worldwide. The global capabilities of CROs will be much needed to evaluate and deliver 21st century medicines.

India's pharmaceutical industry and growing CRO industry have an important role to play in the continuing development of human therapeutics. India's pharma industry is one of the fast-growing sectors of the Indian economy, and its initiatives in biotechnology and information technology position India as a knowledge power and resource for drug development worldwide.

The challenge for India is to nurture and expand the scientific resources that can make it a significant contributor to the new medicine—to use them wisely and safely for the benefit of its nation.

Key Technologies of the New Medicine

Drug Discovery : Genome to Increase Targets 10 Fold

Drug Development : The High-Tech Clinical Trial

Pharmacogenomics : First Step to Individualized Medicine

Pharmacogenomics: The study of genetic variations that affect how an individual metabolizes drugs and responds to therapy.

DNA Testing Will Identify Patient Types:

EMs Efficient Drug Metabolizers
PMs Poor Drug Metabolizers (unlikely to respond)
UMs Ultra-Rapid Drug Metabolizers (may experience side effects)

Use in Patient Treatment:

1. Pretest to predict individual's drug response
2. Adjust dosage to optimise therapy
3. Avoid side effects & ineffective therapy

• Potential
  

1. Improve therapy with existing drugs
2. Reduce adverse drug events (US estimate : 2 Million ADRs; 100,000 Deaths/yr)
3. Develop future drugs for population groups : EMs, PMs, UMs

• Global Medicine : Global Research

People throughout the world need access to new medicines. To develop new medicines, pharma needs access to world populations.

Trends Toward Global Clinical Trials

Scientific Drivers :

Test drugs in affected population (AIDS/Africa; Hepatitis/Asia)
Broader, larger study population (US only 4% of world population)

Regulatory Drivers:

Harmonization of regulation & standards
Acceptance of foreign data

Economic Drivers:

Pressures to reduce time & cost
Need to build new markets

Increasing Capability : Rise of CROs

US 468
UK 161
France 133
Germany 94

INDIA IS AN OPPORTUNITY FOR PHARMA

India's Knowledge Power in Biotech

India is well positioned to become a knowledge power in the new medicine.......

Expertise

India produces a large number of biosciences lab graduates/year Many of bioscience graduates earn PhDs or MAs
In US, Indians account for one-fourth of bioscience workforce

Emerging Industry:

More companies launching biotech initiatives Government focus for development "Genome Valley" breaking ground in Hyderabad

Potential for Cutting-Edge Research:

Example : Stem Cell Research
Reliance Life Sciences of Mumbai has 7 stem cell lines

India's Knowledge Power In Infotech
Informatics:

Domestic pharma companies entering biotech arena are increasing demand for bioinformatics services India has technological expertise India has low-cost advantage
Global market in 2001 $ 1 Billion
2005 $ 3.2 Billion

The Internet:

Future platform for clinical research & treatment India has nearly 5 million Internet subscribers 382 cities & towns have 2,000 or more Internet users 10 Internet companies expected to list abroad or on Indian stock markets by mid 2002

KEYNOTE ADDRESS IN SESSION IV "FINANCING R&D AND BUSINESS IN LIFE SCIENCES" BY DR. S.V.KAPRE EXECUTIVE DIRECTOR SERUM INSTITUTE OF INDIA LTD. PUNE, INDIA

INTRODUCTION

With the sequencing of human genome and improvements in biotechnology the window to unprecedented funding has opened.

The year 2001 brings investors to concentrate on to new therapeutic products developed through the R&D Life Sciences

The technology sector of life sciences in the year 2000 raised an amount of 40 billion USD which is a record in itself.

This is because biologics have decisive advantages over small molecules

This is because they:

• offer attractive growth potential to developers as well as for those who market them.
  
• they are rare
• have superior properties.
  
  
  

MAJOR TECHNOLOGIES THAT HAVE EVOLVED

• CELL CULTURE
  
• ANTISENSE
  
• BIOSENSORS
  
• MONOCLONAL ANTIBODIES
  
• PROTEIN ENGINEERING
• RECOMBINANT DNA
  
  

The table show -
The Therapeutic sector has the most preferred status in the world

The growth of the products of life sciences show -

15% growth in sales
17% growth in market cap

Over 10,000 US Patents granted in 1999

Growth in the next four years expected to reach 40 billion USD

The financing of the life science related business has been mainly through public stock offerings.

Market exploded in the year 2000.

Over US$ 9 BN. raised through IPO (Public Companies) and follow ons.

M& A TRANSACTIONS

• Average deal size for Pharma/Life sciences in US$ 335 MN
  
• And is twice the value of deals over the 4 year period.
  
• Pharma/Life sciences acquisitions are larger value-Pharma companies attempting to increase their R&D capability, product reach using their larger marketing networks.
  

Stock Performance

• Nasdaq Biotech Index - rose by 102% in 1999.
  
• ....Outpacing the 86% rise in the Nasdaq Composite Index
  

Unique Features

• High entry barriers
  
• Primarily driven by R&D
  
• Low Capex
  
• Product Price Insensitivity - Lucrative Margins
  
• Public acceptance of Products
  
• Intellectual Property - Patents % periods of exclusivity
  

Unique Financing Features

• High risk, high return
  
• Long gestation period
  
• - 7 to 15 years
  
• - multifarious test phases
  
• Binary nature of drug/hybrid seed development
  
• Strategic alliances key
  
  • share risks and costs
    
• Importance of market capital
  

Related Issues, Coming Up -

• Access to capital
  
• Access to smart money
  
• Skilled workforce
  
• Access to modern Technology
  
• Time required to get approval from regulatory authorities
  
• IP protection
  
• Domestic market size
  
• Consumer Acceptance
  

Key Success Factors

• Proprietary Expertise
  
• Broad pipeline at various stages of development
  
• Robust lead products
  
• Viable business model
  
• Strong Management
  
• Financial Resources
  
• Patents
  
• Products under clinical trials
  

VC Financing - Trends

• Two deals per partner per year
  
  • 50 business plans a week
    
• 7 year VC period
  
• Raise enough money for growth
  
  • don't fixate on valuations
    
  • VCs as partners, not necessary evils
    
• Globally dozen major VC firms active in Lifesciences show
  

INVESTMENT PRINCIPLES

• Buy enabling technologies
  
  • Companies that have mastered a research approach that will lead to potential blockbusters
    
• Buy products in the pipeline
  
  • Companies with a solid calendar of potential Product Technologies and necessary approvals
    
• Buy Knowledge Resources
  
  • Companies that have high knowledge resources
    
• Buy Promising Stocks
  
  • Companies whose growth stories are promising
    

Link between Lifesciences and Infotech

• Biochips
  
  • Silicon Chips combined with genetic information
    
• Bioinformatics and molecular biology software
  
  • Relational Database, Client-server, Java
    
• Development of extensive databases
  
• Miniaturization of Laboratories
  

LIFESCIENCES (INDIAN OPPORTUNITY)

• STRENGTHS
  
  • Intellectual resources
    
  • Low Costs
    
  • Abundant bio-diversity
    
• OPPORTUNITIES
  
  • Medical/Pharma (Mfg./Contract Mfg.)
    
  • Agriculture technology
    
  • Bio-informatics
    
  • R&D (Contract Research/Inhouse)
    

Role of Financial institutions

• Private/Strategic Equity
  
• Venture Capital Funding
  
• Alliances
  
  • R&D
    
• Marketing
  
• Licencing
  
• Joint Ventures
  
• Mergers & Acquisitions
  
• Strategic Advisory
  

I am grateful to Mr. Shastri of Robobank for granting his consent to use the information stated in the `Investment Banking Perspective on Biotechnology' in this presentation