Advance in biopharma_india_ch_14_shah

Chapter 14:
Application of Recent Advances in
Immunology for Developing Novel
Biotherapeutics in India
Kumar Shah, MD

Advances in
Biopharmaceutical
Technology
in India
January 2008

Editor: Eric S. Langer

BioPlan Associates, Inc.
Rockville, MD, USA

SOCIETY FOR INDUSTRIAL MICROBIOLOGY
Arlington, VA, USA

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and

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Copyright © 2008 by Eric S. Langer

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Editor: Eric S. Langer
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Project Director, Scientific: John Morrow
Production: ES Illustration and Design, Inc.
Text and Cover Design: Esperance Shatarah

Cover photos courtesy of Shantha Biotech

ISBN 978-1-934106-07-5

ii

Acknowledgment
This project would not have been possible without the exceptional efforts of the many people
involved. In particular, we would like to thank:
Yibing (Eliza) Zhou, Project Director, Enterprise
John Morrow, Project Director, Scientific
ES Illustration and Design, Inc., Production Manager, cover graphics.

We would also especially like to thank our reviewers, whose expertise ensured this volume
addressed today’s most important issues:
Prof. P.S. Biesen, Director, Madhav Institute of Technology and Science, India
Prof. Ananda Chakrabarty, University of Illinois, USA
Dr. Thomas E. Colonna, President, Biotech Consultant LLC, USA
Dr. John Curling, President, John Curling Consulting, Sweden
Dr. Milind Deshpande, Technical Director, Fermentation and Processing,
University of Iowa, USA
Dr. P.K. Ghosh, President, Biotechnology, Cadila Pharmaceuticals Ltd., India
Dr. Vijai Kumar, President & Chief Medical Officer, Excel Life Sciences, Inc., USA
Dr. Yennapu Madhavi, Scientist, National Institute of Science Technology and
Development Studies, India
Dr. John Morrow, President, Newport Biotech, USA
Dr. Brandon Price, President. Falconridge Associates, Inc., USA
Dr. Gayatri Saberwal, Scientist, Institute of Bioinformatics and Applied Biotechnology
(IBAB), India
Dr. V.K. Srinivas, General Manager R&D, Bharat Biotech, India
Dr. S. Vsisalakshi, Scientist, National Institute of Science Technology and development
Studies, India
Dr. Scott Wheelwright, President, Strategic Manufacturing Worldwide, Inc., USA

We also extend our sincere appreciation to Shantha Biotech, and Ms. Sravanthi Reddy for her
support and use of cover photos and graphics.

Thank you for your efforts, and your recognition of the importance of this study.

Eric S. Langer
Managing Editor

iii

Preface

T
his study was undertaken, managed and coordinated by BioPlan
Associates, Inc., a biopharmaceutical management and marketing
research consulting firm in Rockville, MD, based on nearly 20 years
experience and knowledge of the market segment. BioPlan surveyed the
industry to identify required content, and then selected subject matter experts
to author relevant chapters to this study.
The Society for Industrial Microbiology (SIM), in recognizing the importance
of applied sciences in biotechnology processes, has lent its name to this
endeavor. The Society for Industrial Microbiology is a nonprofit professional
association dedicated to the advancement of microbiological sciences,
especially as they apply to industrial products, biotechnology, materials,
and processes. Founded in 1949, SIM promotes the exchange of scientific
information through its meetings and publications, and serves as liaison among
the specialized fields of microbiology. Membership in the Society is extended
to all scientists in the general field of microbiology.
India is one of the fastest growing economies in the world. The country has
invested heavily in advancing its pharmaceutical and biopharmaceutical
technologies to improve its healthcare systems, its population’s general health,
and its overall economy.
Both scientists and entrepreneurs in India have made important contributions
to advancing the field at many levels. This study provides a framework from
which both those new to India’s rapid advancements in biotherapeutics and
vaccines, and those with long histories can recognize the potential, and plan
for the future. The findings of this study support worldwide public health and
economic policy.
Each chapter provides unbiased, peer-reviewed perspectives of the current
state of the science and technology associated with biopharmaceuticals in
India. While no single work can encompass all the advances being made in
the field, this study offers a comprehensive assessment of the technological and
economic advancements in India.
The intended audiences include decision-makers at biopharmaceutical
research organizations, biotherapeutic manufacturers, contract manufacturing
organizations, suppliers to the industry, policy-makers, and international
entities evaluating this market. We plan to keep this study current by providing
regular updates as technologies, and the industry advance.

iv

Advances in Biopharmaceutical
Technology in India

Table of Contents

PART 1: Introduction .............................................................vii

Chapter 1 Prospects for Modern Biotechnology in India ....................................................... 1
Prasanta K. Ghosh, Prasenjeet Ghosh, Soma Ghosh, and
Kushal Shodhan

PART 2: State of India’s Life Sciences Industry ......................67

Chapter 2 A Window into India’s Biopharma Sector .............................................................69
Narayan Kulkarni

Chapter 3 Indian Biopharmaceutical System and Policies ................................................109
Yennapu Madhavi, Ph.D.

Chapter 4 Government Support for Biotech and Biopharmaceuticals Industry ..........127
Dr. B.M. Gandhi

Chapter 5 Biopharmaceutical Products in India ..................................................................179
Scott M. Wheelwright, Ph.D., and Hazel Aranha, Ph.D.
Chapter 6 Biogeneric Manufacturing in India ......................................................................203
Ashesh Kumar, Ph.D.
Chapter 7 Biopharmaceutical Market Situation ..................................................................235
Merlin H. Goldman, PhD MBA CEng MIChemE

Chapter 8 The Contract Research Industry in India ............................................................281
Umakanta Sahoo, MBA, Ph.D., and Faiz Kermani, Ph.D.

Chapter 9 Regulatory Landscape for Clinical Trials in India ..............................................313
Romi Singh, Ph.D. and Brijesh Regal
INDIA BRIEF 1 Pre-Clinical and Clinical Trial in India ............................................................................................. 327
V.K.Srinivas, Ph.D

Chapter 10 Life Sciences Education in India...................................................................................333
Dr Dipti Sawant, Ph.D., MBA, CCRA

v

PART 3: Scientific Issues in India .........................................383

Chapter 11 Vaccine Industry in India .......................................................................................385
Dr. Prasad S. Kulkarni, M.D. and Suresh S. Jadhav, Ph.D.

Chapter 12 Development of Plasma-Derived Biopharmaceuticals in India:
Challenges and Opportunities .............................................................................465
John M. Curling, Christopher P. Bryant, Timothy K. Hayes, Ranjeet S. Ajmani

Chapter 13 Bioprocess Expression and Production Technologies in India .......................519
David M Mousdale
INDIA BRIEF 2 Technology Transfer: Impact and Importance for Indian Biotechnology Growth ........ 555
Susan Kling Finston

Chapter 14 Application of Recent Advances in Immunology for Developing Novel
Biotherapeutics in India.........................................................................................563
Kumar Shah, MD

Chapter 15 Early-stage Key R&D Components for Successful Development of
Protein Therapeutics ..............................................................................................589
Krishna M. Madduri, Ph.D.

Chapter 16 Understanding Ayurveda Medicine ....................................................................605
Dr. Sampada Amol Mahajan

PART 4: Biobusiness in India ...............................................619

Chapter 17 Biopharmaceutical Outsourcing: A Comparative Overview of
the Landscape between India and China ...........................................................621
Minna A. Damani

Chapter 18 Biopharmaceutical Research Collaborations between India and
the West: A Guide to Prospective Partnerships .................................................661
Uri Reichman, Ph.D., M.B.A., Bharat Khurana, D.V.M., Ph.D., and
Steven M. Ferguson

Chapter 19 Outsourcing R&D to India......................................................................................723
Probir Roy Chowdhury and Sajai Singh
INDIA BRIEF 3 Outsourcing Biopharma R&D to India........................................................................................... 741
Jim Schnabel, Senior Research Associate, BioPlan Associates, Inc.

Chapter 20 Venture Capital in India Today..............................................................................747
Sajai Singh and Probir Roy Chowdhury

vi

14
Application of Recent
Advances in Immunology
for Developing Novel
Biotherapeutics in India

KUMAR SHAH, MD, President
Amit Shah, Scientific Officer
Department of Research and Development
Endocrine Technology, LLC
304 Livingston Street,
Brooklyn, NY 11217
Phone: 718-222-1065
Fax: 718-852-7412
E-mail: kshahmd@aol.com

Advances in Biopharmaceutical Technology in India

About the Authors
KUMAR SHAH, MD is a Founder and President of Endocrine Technology,
LLC in NY, USA. He has over 20 publications and several patents related to the
modulation of Factor H. He is a Diplomat in Internal medicine, Diabetes, Endo-
crinology and Metabolism. He is in active consulting practice. In India he served
as clinical research physician for Roche Products and acted as a consultant to
initiate “Cell Transplant Laboratory for the cure of diabetes” for the institute of
kidney diseases, Ahmedabad, Gujarat State. He has presented paper in National
HIV/AIDS conferences held in Mumbai (HIV Congress: 11-13th March, 2005).

AMit SHAH is a scientific officer of Endocrine Technology, LLC. He is involved
in developing immune modulation technology of the Company and in the
management of information technology. He has a degree in computer sciences
and research interests in biotechnology field.

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CHAPTER 14 n Application of Recent Advances in Immunology for Developing Novel Biotherapeutics

ABSTRACT

I
mmunity is a major barrier in the translational development of
bio-pharmaceutical drugs. The US Food and Drug Administration
estimates a cost saving of US$100 Million if the human safety of
new drugs could be predicted with 10% accuracy. The recent advances
in the fundamentals of immunology have assigned a host protective role
to Factor H. Factor H is an immune regulatory protein of a billion year
old early human defense system such as Alternate Complement System.
The Alternate Complement System plays a crucial role in activating
host inflammatory and memory responses when foreign material such
as bacteria, viruses, cancer cells, allogenic and xenogenic somatic cells,
biotherapeutics drugs or bioterrorism related organisms interact with
host and its immune system. The potential of Factor H modulation to
develop novel bio-pharmaceutical products to prevent, treat and control
global diseases is detailed. Large drug companies are looking to devel-
oping countries such as India for cost-effective clinical development of
novel biotherapeutic drugs such as vaccines for HIV/AIDS. India offers
the necessary legal and scientific framework for multinational compa-
nies with product patents to develop novel biotherapeutic products
cost-effectively.

565


Application of Recent Advances in
immunology for Developing Novel
Biotherapeutics in india

1. introduction

I
n translational development of biotherapeutic drugs, immunity is a
major barrier.1 The human safety issue remains a problem that affects
companies in both clinical trials and in post marketing phase.2-4 The
drug industry’s problems associated with meeting the regulatory safety and
efficacy standards for new products are analyzed in an FDA report on inno-
vation stagnation published in 2004 (FDA).5 The cost of successful product
from bench to bed-side has soared to US$1.7 billion by 2002. A growing list
of fatal diseases compounds the problem of product pipe line and threatens
the global consumers with next wave of morbidity and mortality from HIV/
AIDS, tuberculosis, malaria, SARS and bird-flu like fatal pandemics along
with evolving threats of bio-terrorism. FDA estimates that if product safety can
be predicted with 10% accuracy, it has potential to save up to US$100 million
in new product development costs. The recent advances in the fundamentals
of immunology have assigned a host protective role to Factor H.6, 7 Factor H is
150 kD immune regulatory protein of a billion year old early human defense
system such as Alternate Complement System. The Alternate Complement
System plays a crucial role in generating host inflammatory responses and is
involved in education, instruction and priming adaptive or memory
responses.8, 9 The potential of Factor H modulation to develop novel bio-phar-
maceutical products to prevent, treat and control global diseases is detailed.10-12

2. immunity as a Barrier in translational Drug Development

H
istorically, the critical event in the development of modern biothera-
peutic drugs was deciphering the double helix structure of DNA in
1953 by Watson and Crick. Since then, recombinant DNA tech-
nology has given birth to numerous biotherapeutics such as recombinant
insulin and erythropoietin. June 26, 2000, another milestone in genetics, is
the day scientists announced the sequencing and assembling of the first rough
draft –about 99% -of the genetic code that makes up the human genome.

566


Novel biotherapeutic products incorporate living cells or subcomponents in the
final product for the prevention, treatment and cure of diseases. This approach
has the potential to tackle a growing number of deadly diseases. Large drug
companies are looking forward to developing countries for the cost-effective
clinical development of novel biotherapeutic drugs such as vaccines for HIV/
AIDS. TRIP implementation in India offers the necessary legal framework for
multinational companies with product patents to cost-effectively develop novel
biotherapeutics.
Biotherapeutic products such as vaccine, recombinant proteins and immune
related drugs including monoclonal antibodies13 is class of drugs experiencing
the fastest rise in the new drug development process. Proteins are dynamic
molecules with the ability to adapt to various environment and physiological
factors. This flexibility allows a protein to transmit information from one
biochemical pathway to another. Changes to the shape of a protein can acti- tRiP implemen-
vate, inactivate, or affect the function of a protein. The importance of sialic tation in india
acid in the proper function of recombinant protein and antibody is increas- offers the
ingly recognized14-16 Recombinant human protein therapeutics; require necessary legal
complex glycosylation, such as sialytation, for stability, solubility, folding, phar- framework for
macokinetics, pharmacodynamics activity and to prevent host inflammatory multinational
reactions. Developing and marketing biotherapeutics based on recombinant companies with
proteins and antibodies or its generic equivalents require specialized dedicated product patents
facilitates of cell culture and fermentation technology. Manufacturing and to cost-effectively
marketing of such products require different mind set and expertise than that is develop novel
generally required for generic drugs.
biotherapeutics.
The biotherapeutics drugs such as recombinant proteins and monoclonal
antibodies have added new layers of complexity and cost to the drug devel-
opment process. For example, there are differences in the sialic acid binding
sites in apes and human. The differences in sialic acid binding between Apes
and human beings apparently has contributed to the occurrence of cytokine
storm or “Acute inflammatory syndrome” in recently carried out human trial
of antibody after it was proved safe in monkey studies. Six healthy young male
volunteers at a contract research organization were enrolled in the first phase
1 clinical trial of TGN1412, a novel super agonist anti-CD 28 monoclonal
antibody that directly stimulates T cells. Within 90 minutes after receiving a
single intravenous dose of the drug, all six volunteers had a systemic inflamma-
tory response characterized by a rapid induction of proinflammatory cytokines
and accompanied by headache, myalgias, nausea, diarrhea, erythrema, vaso-
dilatation and hypotension Within 12 to 16 hours after infusion, they became
critically ill, with pulmonary infiltrates and lung injury, renal failure and
disseminated intravascular coagulation. After intensive hospital therapies all six
patients survived.
The full safety profile of a drug is rarely known at the time of approval by the
Food and Drug Administration (FDA). Most drug-development programs are

567


designed for the treatment of symptomatic indications are under powered to
detect any increased risk of rare drug reactions or change in background event
rates attributable to the drug. Large, post marketing, randomized, controlled
trials provide robust data on drug safety but are subject to multiple source of
bias. Observational studies of a drug’s effects in clinical practice can offer addi-
tional information on risks. Post-marketing observational studies permit the
evaluation of drug safety in large number of patients in a real world setting,
where practice patterns, including off label use of his drug can be assessed.
Aprotinin was approved by FDA in 1993 as a mean of reducing periopera-
tive blood loss in patients undergoing coronary artery bypass grafting. Neither
the clinical trial database nor the numerous randomized controlled clinical
trials conducted after approval identified an association between aprotinin and
any short term increase in the risk of death or nonfatal cardiovascular or any
Due to the serious renal toxic effects.
differences in Overwhelmingly, the drug development process involves two dimensional
sialic acid binding, models of in-vitro screening of chemotherapeutic drugs for efficacy against
the successful pathogens and cancer cells. Such screening efforts do not take into account
results from small the third dimension that is how the drug will behave once it is introduced in
and large animal warm blooded animals. Immune response is different in small animals, large
model often are animals and in human models. The drug interacts three dimensionally with
not translated host and its immune system most strongly in humans. Sialic acid binding is the
into human safety common point of interactions. Due to the differences in sialic acid binding, the
and success. successful results from small and large animal model often are not translated
into human safety and success. The host immune system reacts with endo-
toxins, foreign proteins, antibodies and cells to induce inflammatory responses
where sialic acid variations and its interactions with the alternate complement
system are common denominators. Table 1 summarizes the role of immunity
as a barrier in the translational development of drugs.

3. the Changing Role of Fundamentals of immunology:

T
he studies on immunity during the last few decades have mostly
concentrated on the adaptive response in immunology and its hall-
marks, that is, the generation of a large repertoire of antigen–recogni-
tion receptors and immunological memory that relates to cellular and antibody
responses. Current understandings of immunology are not complete and
over the period of time have undergone numerous revisions 17-19 Therapeutic
immune suppressive drugs developed and based on above understandings are
extremely toxic, have many adverse effects and are associated with increased
risk of infection and tumor potentials.20
Recent anthrax event prompted the preparation of a document titled “Stra-
tegic Plan for Bio-defense Research” in 2002 by Anthony Fauci, Director of
National Institution of Allergy and Infectious diseases (NIAID) branch of
National Institute of Health (NIH) in USA (http://biodefense.niaid.nih.gov).

568


tABLE 1: immunity in drug development

S NO PROPERtiES PHARMACEUtiCALS BiOtHERAPEUtiCALS NOVEL BiOtHERAPEUtiCS
1 Type of Drugs Synthetics Derived from live cell Combined with Live
Cell or its Component
2 Molecular Size Small Large Variable
EX: 1.Vaccine
1.Recombinant Proteins 2.Cell Transplant
2.Antibodies
3 Drug Discovery Structural Analogs Cell Culture System, IN-VIVO
of synthetic Fermentation Combination
compound Technology of cell or its
By PhD (IN VITRO) Components
scientist /chemist
4 Product short life Long Short sensitive Shorter
to temp changes Sensitive to temp
Changes
5 Adverse Effects Hapten based 1.Endotoxin 1.Endotoxin
(Immune 2.Sialic acid difference 2.Sialic acid difference
Related)
3.Early Immune reaction 3.Allo/xenogenic
4.Infection Risk
5.Early Immune Related
6.Delay Immune Related
6 COST <US$1 billion >US$1 billion >US$1.5 billion

From a scientific and medical perspective, this plan is best seen as a variant of
the general problem of emerging infectious diseases that have central char-
acteristics of high morbidity and mortality due to inadequate diagnostic and
therapeutic interventions. The document highlighted the need to study three
dimensional interactions of microorganisms with host and its immune system.
It was acknowledged in the document that this is the field where experts lacked
in-depth understandings. The plan emphasizes the importance of gaining a
better understandings in the three dimensional interactions of how pathogens
interact with the host and its immune system. The investments were justified
by pointing out that such a research and development plan will have potential
spin off applications in immune related diseases of developed countries such
as in transplants and autoimmune diseases. The research will extend benefits
to immune related diseases of developing countries such as in their fight
against Tuberculosis, HIV and Malaria. It was suggested that international
cooperation with developing countries will facilitate the development of such
therapeutics.

569


One of the major failing of the fundamentals of immunology is incomplete
understandings as to how the immune system protects itself when acti-
vated against foreign intruders. Currently scientists believe that the host is
protected because of the presence of immune regulatory receptors in the
cell membrane.21 In humans, immune regulatory proteins embedded in the
host membrane are encoded by a cluster of genes located on the long arm of
chromosome 1 (1Q32). This region is called as the regulator of complement
activation (RCA) gene cluster. Although the proteins within the RCA family
may vary in size, they share significant primary amino acid structure similari-
ties. They are organized in tandem structural units termed as short consensus
repeats (SCRs). The evolutionary relationships suggest membrane bound RCA
proteins are functionally related.
The recent advances in immunology have shifted attention to the working of
in humans, early human defense systems and the potential to educate, prime and develop
immune memory based immune responses. Evolutionary immunologists date innate
regulatory or natural defense system back 700 million years or more. The complement
proteins system is an ancient microbial defense system. This is a system of fluid prote-
embedded in the ases that interact with immune cells and its receptors to protect human beings
host membrane from ancient time against foreign intruders. The individual fluid proteases are
are encoded numbered C1-C9. The complement system has three ways to activate and
by a cluster of augment human defense system. One is antibody based that lead to the acti-
genes located on vation of classical complement system. The second approach is lectin based
the long arm of that is activated in response to presence of lectin based pathogen recogni-
chromosome 1 tion molecules and third is through Alternate Complement system. As shown
in Figure 1, the objective of three pathways of complement system, C3 is to
(1Q32).
generate common molecule C3. According to the recent advances in Immu-
nology, the innate complement system differentiates self, and non-self, through
generation of common molecule C3 and its active catalyzed product C3b.
C3b is constantly generated in body fluid due to “enzyme tick-over hypoth-
esis” by Alternate Complement System. If non-self or bacteria is identified
because of carbohydrate signature it carries, C3b preferentially binds to Factor
B to generate C3bB. This is further acted upon by Factor D to generate C3b
convertase, C3bBb. Factor D is 25 kD immune activating circulatory protein
of Alternate Complement System. It is mainly synthesized in adipose tissues.
It also amplifies the activated responses of Classical and Lectin based comple-
ment system. Factor H now regulate the complement activation by breaking
down C3bBb to inactive C3bH. Active C3 fragmented products, C3a-C5a
and C5b-C9, membrane attack complex have inflammatory components and
stimulate the production of inflammatory cytokines. C5b-C9 in addition has
cytotoxic component that form membrane attack complex and cause cytolysis.
C5b-C9 cytotoxic immune responses are fluid counter part of cellular cyto-
toxic immune responses initiated by Natural killer cells. Factor H also act as
a controlling point in the amplifying cascade and is involved in inhibiting

570


C3
C3
C3b

Factor B Ab

C3bB
NK cells B cell +
Factor D

C3bBb C5b-C9

CYTOTOXIC Th 1 cells
Factor H Th 2
RESPONSES

C3bH
CD8T
Factor I cells CD4T

+ IC3b C3a-C5a

Phagocytosis CD4 Mature

CD4 Immature

Activation of Human Defence Responses
+
IC3b Breakdown Product Costimulate B Cells

Figure 1: Recent advances in immunology

Legend: Figure 1

1. C3, three activating pathways of the complement system vis: Alternate, Lectin-based and
Classical complement pathways
2. C3, Common end product of 1.
3. C3b, an activated C3 with thioester bond removed.
4. Factor D, serine protease activiating protein of Alternate complement activating pathway
5. C3bBb, C3 convertase that flag foreign pathogens
6. Factor H, complement regulatory protein that has been assigned new role of recognizing
self, host tissue as per recent advances in immunology. Microbes pirate this protein to mask
its identity as self.
7. C3a-C5a, activating intermediary complement products with host inflammatory actions.
8. Macrophage, also CD 4 or immature dendritic cell in which entry of bacteria is facilitated
through its surface receptors.
9. CD 4 T matured dendritic cell where processed pathogen by 8 through phagocytosis express
foreign signal by depositing peptide fragments in MHC 1 and MHC 11 groove
10. CD 4 T cell of adaptive immunity that sense foreign signal according to “two Signal hypoth-
esis”.
11. Th 2 subtype of CD 4T cell that is involved in humeral cellular responses.
12. Ab, antibody that is formed by stimulation of B cells by 11.

571


the formation of “Membrane attack complex” and at the same time inacti-
vating C3b. The inactivated products of C3b such as iC3b, C3d, C3dg etc
act as opsonin or natural adjuvant that attach breakdown products of foreign
pathogen. Both inflammatory cytokines and natural adjuvant help in the
maturation of dendritic cells by expression of co receptor function such as B
7 molecule. This according to “Two signal hypothesis” prime T cell responses.
Another route by which iC3b and its breakdown product are involved in
priming antibody responses is by acting as a natural adjuvant by binding to B
cell receptors that amplify plasma cell function. Both T and B cell responses
are involved in generating memory responses.
In the absence of foreign pathogen, C3b binds with Factor H to form C3bH.
Factor H mainly bind to sialic acid binding sites on the host cell surface.
Factor H is a circulatory complement regulatory protein of Alternate Comple-
Both t and B ment System. It has unique structure of twenty short consensus repeat (SCR)
cell responses domain. Each SCR contain approximately 60 amino acids. Factor H is heavily
are involved glycosylated and has high sialic acid content. Factor H is the key self- recog-
in generating nition protein that discriminates host –like features on microorganisms and
memory generate spectrum of activation rates for the complement system in different
responses. microorganisms. A central question in innate immunity is how its various
systems distinguish between potential targets and hosts. Factor H uses its 20
SCR domains to search for and interact with many ligands on a given target.
Each SCR domain contributes to the recognition pattern, and if these sites
work cooperatively in the groups of twos, threes and fours, etc, then by simple
combinational math Factor H would have ability to discriminate among over
106 target surfaces. In the absence of foreign pathogen C3b does not form
C3b convertase.
The importance of recent advances in immunology emphasizing shift to early
human defense system and is ability to educate, initiate and prime delayed
adaptive immune responses is summarized in Table 2.
The dominant role of circulating immune regulatory proteins to protect host
cells against activated immune system is slowly being recognized. In evaluating
the structure-function relationship of circulating immune regulatory proteins
with membrane bound proteins, a study of genes involved in the regulation
of complement activation (RCA) is particularly instructive. Both membrane
bound and circulatory immune regulatory proteins are related. However, circu-
latory immune regulatory immune proteins appear to be a dominant compo-
nent in this relationship.

572


tABLE 2 Recent Advances in the Fundamentals of immunology

Complement System Pathways
S NO PROPERtiES CLASSiCAL LECtiN ALtERNAtE
1 RECOGNITION Ab-Complex MBL-Carbohydrate C3b-Microbe
2 COMMON MOLECULE C3 C3 C3
3 AMPLIFICATION ALTERNATE PATHWAY ALTERNATE PATHWAY ALTERNATE PATHWAY
4 REGULATION FACTOR H FACTOR H FACTOR H

tYPE FUNCtiON SiGNiFiCANCE
5 EFFECTOR 1.C3b Convertase Tagging of foreign Pathogen
particle-
RESPONSES 2.C3a-C5a Chemo taxis Inflammation
3.C5b-C9b Cytotoxic Cell Lysis
4a.C3b CR1 Binding
4b.iC3b CR3/CR4 Binding
4c.C3d CR2 Binding
6 ADAPTIVE 2+3 of item 5 T Cell Responses Memory Responses
RESPONSES 4a to 4c of item 5 B Cell Responses Memory Responses

4. the Market Opportunity:

I
ndia is increasingly being promoted as an outsourcing destination for the
development of biotherapeutic drugs. The advantages cited are lower
costs, and shorter time duration for development of new drugs.22-23 The
United States market is the most matured and advanced in terms of patent
laws, drug development process, regulatory oversight to protect public safety,
the market approval of drugs, and reimbursement systems. The US market
is therefore most lucrative for novel drugs. The US has a health care cost of
$ 1 trillion in the year 2000. This cost will climb to $2.3 trillion by 2015.24
TRIP implementation in the developing world coincides with the loss of
patent protection on numerous drugs and biotechnology products in US. This
provides new incentives for drug companies in developing countries. India’s
manufacturing and formulation experiences over the past three decades comes
in handy for generic drugs where patents have expired. The cost of new
drug discovery and its clinical trials are soaring. The cost structure to develop
new drug in developed world is very high. Multinational drug companies are
therefore moving to developing countries to lower their costs and to tap new
markets. The drug companies in developing countries have tremendous incen-
tives to rapidly adapt US based regulatory standards and business norms. The
compliance by drug companies will facilitate their participation in developing
and manufacturing generic and biogeneric drugs for developed markets. It

573


will help them to form collaborative partnerships with multinational drug
companies and outsource their needs for new drug discovery, clinical trials,
manufacturing and marketing. Developing countries such as India and China
are experiencing rapid expansion of their health care markets. The consumer
base in China and India covers 30 % or more of the global population. The
ongoing trend to outsource medical care from the developed world to the
developing world has accelerated. Both are adding new market opportunities
in developing World. There are over 4000 biotechnology companies globally
trying to compete to develop safe and effective products. By 2015, as TRIP
implementation extends to under developed countries, the drug companies
globally will compete for expanding market share.
A critical insight or an improved understanding of human biology, particularly
in the fundamentals of immunology for example at the molecular level have
the consumer the potential to improve safety of drugs in translational drug development
base in China and program and also has the potential to provide better solutions to diseases that
india covers 30 affect global populations. In the modern drug development process immunity
% or more of the is a common barrier for current and future therapeutics. As pointed out earlier,
global population. circulating immune regulatory proteins such as Factor H bind to the poly
anionic or sialic acid residues present on the host cells. Factor H along with
membrane immune regulatory receptors neutralize activated immune proteins
on the cell surface. Bacteria and viruses co-evolved with human existence.
They constantly fight with human defense system for their survival advan-
tages. The presence of sialic acid content in their cell membrane allows them
to mask their identity as self. Many bacteria and viruses such as avian, feline,
murine and simian RNA viruses are inactivated and lysed by human serum. In
recent years, a large number of bacteria, viruses, parasites, and cancer cells are
identified that pirate the functioning of human defense system by binding to
the circulating immune regulatory protein or its downstream breakdown prod-
ucts. This is due to their sialic acid content. Therapeutic modulation of Factor
H and its potential to develop novel biotherapeutic drugs in different diseases is
detailed as under.

5. therapeutic Applications of Factor H modulation
A. Atypical Hemolytic Uremia Syndrome (aHUS):

H
emolytic Uremic Syndrome (HUS) is a severe disease frequently
leading to end stage renal failure. Clinical features include rapid
deterioration of renal function, anemia, low platelet count and frag-
mented red blood cells in the blood.
Current classification of HUS delineates two major types. Classical HUS
occurs almost exclusively in childhood and is caused by bacteria releasing
Shigela-like toxins. The disease starts with signs of enteritis, generally initiated
by Escheria Coli strains, mainly 0157. Atypical HUS (aHUS) usually occurs
in adults, and has been reported in association with a variety of conditions

574


such as therapeutic drug usage (Ovulation inhibitors and immunosuppres-
sive drugs) diseases such as malignancies and systemic lupus erythramatosus),
Pregnancy and after child birth. Familial occurrence of aHUS is reported in
siblings and in a few families with autosomal dominant inheritance and rarely
with autosomal recessive transmission. According to one study of 111 patients
with aHUS, 14 % patients had FH1 germ line mutations.25, 26 To understand
the dominant relationship of circulatory immune proteins over membrane
bound immune regulatory proteins, it will be useful to consider what happens
in the absence of Factor H. Congenital deficiency of Factor H or its mutation,
leads to the activation of Alternate Complement System due to unopposed
action of Factor D. Since activated immune proteins are either not inactivated
or partially inactivated by membrane immune regulatory proteins, it leads to
“Atypical hemolytic uremia syndrome” (aHUS). The therapy at clinical level is
to replace Factor H that is mainly synthesized in liver. An alternate approach there is a
is to inhibit activated complement system such as by modulation of Factor H. perception that
Thus Factor H modulation could be life saving in these patients. successful drug
B. HIV/AIDS Therapeutics: companies with
i. The Role of India: There is a perception that successful drug companies novel products
with novel products such as an HIV vaccine must balance ethics and morality such as an HiV
in business practices, and issues of profiting from deadly yet preventable and vaccine must
treatable diseases such as HIV must be considered. This has played a role in balance ethics
encouraging India generic drug companies to take advantage of the Indian and morality
patent laws of the 1970s that allowed them to meet growing public demand in business
for cost-effective medicines. It is a surprise to many people including Indian practices…
government officials that it is estimated there are close to 6 million HIV
patients in India and. HIV is expected to grow four folds to 25 M by 2025.
There is an added risk that 50 % of these patients will have reactivated tuber-
culosis that may be resistant to currently available drugs. Since half of HIV
patients in developing countries may harbor tuberculosis that may be resis-
tant to multiple drugs, the future scenario of public health in India is a chal-
lenge. In March 2005, the Indian parliament passed the third amendment to
the Indian Patent Act (1970) that led to the introduction of “Product Patent
regime”. This has raised serious questions regarding the role of generic drug
industry and its ability to compete and at the same time provide the continuing
availability of essential medicines at affordable prices.
ii. The Dilemma of Brand vs. Generic Drugs: New drug development
in developed countries is costly. It is a high risk venture that takes 10-15 years
of sustained effort. The chances of success is only 30 % after animal tests are
completed. In 20th century the traditional pharmaceutical industry played a
dominant role in the control of major infectious and chronic diseases. This
reduced greatly the morbidity and mortality for example HIV/AIDS in devel-
oped countries. The high charges for new medicines by major pharmaceutical
companies were justified in developed countries. The medical management

575


of patients in developed countries is supported by adequate reimbursements
for new technology and patented drugs. Perhaps, the high reimbursement
rate and profits in developed country could be used effectively to innovate at
marketing level to lower the cost of drugs through outsourcing. However, high
cost drug models in developing and under developed countries is problematic.
There are no adequate laws to protect patented inventions. There is no reim-
bursement mechanism for marketed patented products. The ongoing drama of
affordability of essential medicines for example in HIV/AIDS is played out in
major news papers.
In the 1970s India introduced product process patent laws. The laws were
mainly geared to stimulating competitive capabilities of local drug industries.
It was an enormously frustrating experience at the regulatory level to introduce
advanced products based on Western patents. Indian patent laws of the 1970s
[t]he indian provided a way for Indian drug companies to do what was legally allowed:
drug companies copy patented products by bypassing the manufacturing and drug development
reduced the process. From a regulatory point of view the generic drug company only needs
cost of drug to prove that their products are bioequivalent to patented drugs. Thereby, the
development Indian drug companies reduced the cost of drug development to 1/1000th of
to 1/1000th of patented cost. This allowed the Indian drug industry to flourish in developing
patented cost. and third world countries. It allowed them to compete with multinational drug
companies effectively. Copied products were marketed at a fraction of the cost
that was charged by multinational companies. This benefited consumers to
meet their dire needs for products that were safe, low cost and quality based.
In the public eyes generic drug companies were perceived as benefactors of
humanity and multinational drug companies were branded as exploiters of
human rights.
Despite scientific progress and therapeutic advances –cost ineffective medicines
and cheap generic counterparts have proliferated and the demand –supply gap
for truly life saving drugs have widened. This is a true international emergency
of the 21st Century. Leaders around the world are scrambling to find mean-
ingful solutions to contain the rapid global spread of infectious disease such as
HIV/AIDS.
iii. The Adverse Impact of Patent laws of 1970s: The patent laws
of the 1970s included controversial Section 5(1) which provided for process
patents and stifled innovation in India. There is no market mechanism to
adequately reimburse patented products. The invention and discovery of new
drug development is considered costly, economically not viable, and wasteful
of time, money and energy by academic centers, financial centers and experts
in India. This inertia is reflected in poor venture capital investment in research
and development of new drugs. The hospital system, the education system and
medical industry in general remained apathetic and negligent in their mission
objectives to serve humanity. Availability of cheap drugs and lack of appro-
priate reimbursement mechanisms or insurance system led to the neglect of

576


medical illnesses and its follow up in developing countries. This has put India
innovation several years behind developed countries.
iv. New Patent regime in India: The Indian parliament’s third amend-
ment to the Indian Patent Act (1970) that led to the introduction of “Product
Patent regime” raised serious questions regarding the role of generic drug
industry and its ability to compete and at the same time provide the continuing
availability of essential medicines at affordable prices. The recent introduc-
tion of Trade related intellectual Property Agreements (TRIP) is intended to
correct the past imbalance by creating level Plainfield where an individual or a
small company can compete with giant drug companies based on intellectual
properties.
In the US, the patent process is governed by ’Prior User’s right’ while in
Europe it is governed by ’First to file’. The typical requirement for an invention
patented in the US is that it has to be useful, new and not obvious.27
India have adapted Trade Related Intellectual Property Agreements (TRIPs)
and raised the bar for patented inventions to avoid spurious claims. In order
to develop successful patent under section 2 (i) (j) of Indian patent act, a new
definition for “new invention” has been added. ‘New invention’ is defined as,
“any invention or technology which has not been anticipated by the publica-
tion in any document or used in the country or else where in the world before
the date of filing of the application with complete specification, i.e. the subject
matter has not fallen in public domain or that it does not form part of the state
of art”.

Patents and Gleevec:
Gleevec (spelled Glivac outside the United States) is used to treat chronic myeloid leukemia. This
drug has been patented by a multinational drug company in 35 countries and is sold for $26,000/
year. The drug was rejected in India under section 3(d) and is a subject of ongoing legal battle.
Gleevac, the brand name version of imatinab mesylate is offered by generic drug companies at
1/10th price by obviating the need for clinical trials. (28).
Under the amended section 3(d) of Indian patent act the mere discovery of new use, new property,
use of a known process, machine or apparatus or combination of two products is not patentable if it
does not result in new product with increased efficacy of known compound. According to current
Indian patent laws not patentable clause under section 3 (i) include “any process for the medicinal,
surgical, curative, prophylactic, diagnostic or therapeutic or other treatment of human beings or
any process for a similar treatment of animals to render them free of disease or to increase their
economic value or that of products.”

577


With reference to the inventive step, the Indian Patent Act states:
“‘Inventive step’ means a feature of an invention that involves technical
advance as compared to existing knowledge or having economic significance or
both that makes the invention not obvious to a person skilled in the art”.
The off label use of the drug can be patented as method of treatment in devel-
oped countries. It is stated that medical –process patents threaten to complicate
medical practice, increase cost, and restrict access to new procedures. Owing
to such concerns, nearly 80 countries refuse to grant patents on medical proce-
dure.29 Adaptation of US patent laws of ’Prior user right’ as opposed to ‘First
to file’ European and Indian patent laws have the potential to remove abusive
practices and may contribute to healthy industry competition. The patient
is benefited by having access to needed drugs and the industry experiences
healthier competition. The outcome of the implementation of TRIP laws in
[P]atients with
India is that in August and September 2006, patients with cancer, lawyers for
cancer, lawyers
patient advocacy groups, and representatives of nongovernmental organiza-
for patient
tions (NGOs) converged on the offices of a multinational drug company in
advocacy Mumbai, India, to protest the company’s efforts to obtain an Indian patent.
groups, and This situation where novel applications of an established drug, in a new formu-
representatives of lation and in new devices is of growing importance with the rapidly rising
nongovernmental cost of drug development in resource limited country such as India. There is
organizations an urgent need to develop innovative and new solutions at the clinical level.
(NGOs) converged Although, most physicians are allowed to use established drugs for new appli-
on the offices of cations, in a given patient the safety and efficacy of the off label drug use
a multinational remains questionable. If an off label drug in a new formulation is effective in
drug company in a fatal disease – there is nothing wrong in patenting the drug and it should be
Mumbai, india, welcome. From regulatory perspectives, the drug authorities have taken a stand
to protest the to allow the use of such drugs only after adequate clinical trials. This has a
fixed clinical trial cost. The off label uses of the drug for new disease applica-
company’s efforts
tions either in existing or new formulation is a commercial activity. Another
to obtain an
important step taken by US FDA is to punish the drug company with severe
indian patent.
penalties for promoting the off-label use of drugs to physicians. Since clinical
trials of a drug itself is a costly enterprise, there is very little incentive on the
part of physicians or the drug industry to undertake large clinical trials to
assess the importance of existing drugs in new deadly diseases unless they can
patent it and prevent competition from generic companies. Patenting of new
applications of existing drugs in new formulations is the fastest way to generate
new therapeutic drugs at cost effective prices. It obviates the need for manu-
facturing that can be outsourced. This can result in saving of US$200 million
in up front cost. According to the US FDA, if the safety of the drug is known
or if it can be predictable by 10 % it has potential to save US$100 million in
drug development costs. The existing drug in new formulations has predictive
potential of safety by at least 50 %. This should reduce the cost of drug devel-
opment by US$500 million.

578


In the era of new patent regimes, the mindset of Indian drug companies and
government organization is tuned to serve the need of multinational drug
companies as outsourcing partner and offset the impact of TRIP by finding
new opportunities in the developed world. A large number of patented drugs
that have annual sales of over US$100 billion in the US face expiry of patents.
This is a new opportunity for Indian drug companies to compete internation-
ally in developed countries for the generic drug market. Implementation of
TRIPs coincides with the global explosion of knowledge. India has proven
expertise in the management of information technology and its evolving tools.
It is this leadership that is combined with patented technology that is helping
Indian companies to handle knowledge base at global level. This is defining the
new levels of competition and cooperation to gain new leadership role in the
fight against global diseases.
v. Factor H Modulation for HIV Therapy: Responding to the rising A large number
problem of drug resistance, experts have opined for the need for better, simpler of patented
and safer drugs that target the HIV genomic structure in a novel way and at drugs that have
multiple points so that the risk of resistance obtained with current antiretro- annual sales of
viral drugs could be reduced.30 Another leading expert in immunology has over US$100
commented that in view of the limited therapeutic efficacy of current Highly billion in the US
Active Anti Retroviral Therapy (HAART) regimes, there is an urgent need face expiry of
to combine such therapy with immune based approaches that may improve patents. this is a
therapeutic efficacy of cocktail therapies.31 The modern drug discovery begins new opportunity
with genomics and proteomics. Thus for example the role of proteomics is for indian drug
evaluated to identify HIV-1 therapeutic targets in host proteome. Identification companies to
of novel targets for therapy that may not develop resistance is sorely needed. compete…
Therefore, the effects of Tat protein on cellular gene expression during various
phases of the cell cycle of HIV replication have been studied. This has led to
identification of several host proteins including Factor H that may offer novel
therapeutic target.32 In the basic science literature the in-vitro experiments
done with serum of HIV patients has shown that Factor H modulation kill
HIV outside the immune cells.33 The recent advances in the fundamentals
of immunology have identified the growing importance of Factor H in host
protection. Factor H is an immune regulatory protein of Ancient human
defense system, Alternate Complement System. Factor H is pirated by HIV
while simultaneously it also activates complement system. The combina-
tion of piracy of Factor H and activation of complement system allows HIV
to neutralize and prevent the generation of fluid based cytotoxic immune
responses. The breakdown products of immune activation play an important
role in persistence of HIV infection in HIV treated patients and contribute
to future resistance pattern.34, 35 Factor H modulation therefore has potential
to prevent, treat and cure HIV. 36 However, the translational development of
an antibody therapy is problematic. Differences in sialic acid between apes
and human beings may precipitate ’acute inflammatory syndrome.’ Similar

579


syndrome may also be precipitated with the development of Factor H anti-
body. The congenital deficiency of Factor H leads to Atypical acute hemolytic
uremia syndrome (aHUS) characterized by hemolysis, hypotension and renal
failure. A novel therapeutic approach that inhibit Factor H while regulating the
activation of Factor D is urgently needed to overcome above risk and enhance
safety of novel biotherapeutic products.
Figure 2A details how HIV pirates the functioning of human defense system.
HIV is an enveloped virus and has allo MHC 1 and MHC 2 proteins of
the primary host as well as the immune regulatory machinery on its surface
membrane. Once HIV enters the host body, it is efficiently sensed by comple-
ment system. Both Classical and lectin based complement system is activated.
This effort is amplified by Alternate complement system to generate C3b
Convertase, 11, 12 and its down stream products such as C3a-C5a and C5b
to C9. However, HIV simultaneously binds to circulating Factor H on its
surface to form C3bH-HIV, 13 that inactivate C3b Convertase on its surface to
prevent C5b-C9 cytotoxic immune response. The exact details of HIV binding
site to Factor H has been detailed and appear to be on gp 120 as well as on gp
41. C3a-C5a draws immune cells to inflammatory sites to cause host damage,
14. The inactivated C3b products are used as natural opsonin to bind to HIV
particle. Inflammatory milieu is used to facilitate HIV entry inside CD 4 cells.
HIV multiplies and repeats its cycle of freshly infecting new immune cells.
Inactivated C3 products such as iC3b and its breakdown products along with
C3a-C5a that normally prime dendritic cell maturation is circumvented by
HIV. HIV uses complement breakdown products as opsonins and use comple-
ment receptors on the cell surface also to shuttle to follicular dendritic cells
and persist there. This is the underlying mechanism for the failure of HAART
regime. The crucial role played by Factor H in protecting HIV is evident if
HIV is incubated in Factor H depleted sera from HIV patients. The absence
of Factor H leads antibodies of HIV to sense the presence of HIV as foreign
molecule and leads to prompt cytotoxic immune response to kill HIV outside
the cell in the serum with 80% efficiency. Use of membrane bound immune
regulatory Antibody, however brings only marginal improvements. Several
new advances in the understanding of microbial interaction with Factor H
have occurred. One critical problem is how one will control the prevention
of atypical hemolytic uremia. One approach is controlled manipulation of
Factor H and Factor D by developing a fusion molecule. Such an approach
will lead to inhibit Factor H while preventing the over activation of Factor
D. Dual strategy should work well to improve current methods of HAAART
therapy. One potential advantage is by targeting immune evasion mechanism,
the future risk of mutation and potential outbreak of new viruses could be
prevented.
As shown in Figure 2B, HIV interacts with Factor D, Factor H and CD 4 T
cells. Therapeutic strategy aimed to control Factor D will reduce host related

580


Self C3 Non-self (Level of Hierarchy)

Factor H Factor B
C3bH-HIV C3b C3bB
11
Factor D Aborted

C3bBb
12

C3bH-HIV
New HIV 13

Host Damage
14

DC Immature
15 CD 4 Cell

DC Mature
Aborted
CD 4 Cell

T Cell Memory Aborted
Response
Figure 2A: HiV piracy of Factor H

C3

C3 Ab

C3b B cell

Factor D

C3bBb HIV Th 2

Factor H

C3a-C5a CD4T

CD4 Mature
Host In ammation

CD4 Immature

Figure 2B: HiV piracy of Factor H

581


inflammatory damage by HIV and will prevent its persistence in follicular
dendritic cells. This strategy will improve outcome of HAART regime. The
persistence of HIV and the risk of resistance can be reduced. An alternative
strategy is to inhibit Factor H to stimulate Alternate complement system. Since
in blood of HIV patients there are already circulating Antibody, removal of
Factor H will unmask the identity of HIV as foreign pathogen. Circulating
Antibody will initiate cytotoxic immune responses to kill HIV. Incorporation of
this strategy in most modern vaccines will lead to expedient solution to HIV/
AIDS crisis.
Figure 3 shows the interaction of HIV with Factor D and Factor H is outside
the CD 4 cells. Thus Factor H modulation will kill HIV outside the cells while
protecting host from undue activation of Factor D.

Figure 3

582


5 C. HIV Vaccine and its Availability:
Historically, vaccination is the best method of preventing infection.37, 38 Among
the difficulties confronting researchers are viral heterogeneity, the lack of
practical animal model and ethical dilemmas involved in conducting primary
prevention trials in the United States and abroad. India is being promoted as
an outsourcing destination to develop novel biotherapeutic drugs. Interna-
tional Association of Vaccine (IAVI) has spearheaded the project to do HIV
vaccine trials in India. A large number of drug companies have responded to
this call and are heading to India to initiate vaccine trials. HIV/AIDS vaccine
is a reference example of novel bio-therapeutic product that includes a compo-
nent of viral particle. The critical problems are the ethics, human rights and
need to protect volunteers. HIV has sialic acid binding sites. This binding
site is in the cell membrane and is located at gp120/41. This apparently has
resulted in the difference in simian virus and HIV in human beings. Thus for india is being
example, Simian virus doesn’t progress to AIDS in monkeys. The vaccine for promoted as
HIV developed and tested in monkey model has yet to prove its clinical merit an outsourcing
in human trials. In human beings HIV readily progress to AIDS. The vaccine destination to
data generated in monkeys therefore is not predictive of its capability to block develop novel
or prevent progression of HIV to AIDS. Most modern HIV vaccine efforts are biotherapeutic
generated to develop vaccine responses that target Gp 120/41. However, due drugs.
to Factor H binding, they are not able to generate antibody responses. This
is the reason for current failure of HIV Vaccine to induce cytotoxic immune
responses.
The crucial role played by Factor H in protecting HIV is evident if HIV is
incubated in Factor H depleted sera from HIV patients. The absence of Factor
H leads antibodies of HIV to sense the presence of HIV as foreign molecule
and leads to prompt cytotoxic immune response to kill HIV outside the cell in
the serum with 80% efficiency. Use of membrane bound immune regulatory
Antibody, however brings only marginal improvements. One potential advan-
tage is by targeting immune evasion mechanism, the future risk of mutation
and potential outbreak of new viruses could be prevented. On the basis of this
data, Factor H modulation is considered by experts as novel “Complemen-
tary AIDS Vaccine.39, 40 Since in HIV vaccine trials ethics is a major concern,
Factor H modulation is a stand alone HIV Vaccine approach where there is no
HIV particle is incorporated.
D. Age-related macular disease:
One additional approach to drug discovery is information- Information of
specific genes and its related proteins. These tools begin with bioinformatics
and exploration of public gene bank data sites. To create a protein, messenger
RNA (mRNA) – a copy of one DNA strand of a gene – is sent out of the
cell’s nucleus and into cytoplasm, where protein is synthesized by ribosome
that recognize and link to gather specific amino acid chains that make up a
protein. Single Nucleotide Polymorphism (SNP) is a technique to study genes

583


and its variations in amino acid and mutation. In the spectrum of blindness,
few rival Age-related Macular Disease (AMD). With aging population, AMD is
rapidly identified as novel area for drug development by multinational compa-
nies.41 Modern drug discovery efforts have expanded to take advantage of new
discovery tools of genomics.42-44 Macula is the portion of retina that perceives
the sharpest external image. With aging, the cells of macula undergo degen-
erative changes. The whole mark of AMD is an inflammatory lesion called as
Drusen’s lesion. Several drug companies have products under development to
inhibit the molecular target identified as angiogenesis. However, therapeutic
manipulation of this target is applicable to less than 10% of advanced cases
limiting therapeutic efficacy and market size. Several large scale trials have
found that in 50% or more cases of AMD, Factor H is mutated leading to the
activation of Alternate Complement System.
the globalization E. The Cure of Type 1 Diabetes:
trends along with
The use of recombinant insulin, its novel formulations and newer better oral
rising standards hypoglycemic agents have improved therapeutic results in the management of
is creating eating diabetic patients. However, these efforts have not cured diabetes. It is not only
patterns that is a disease of developed countries but also a major problem in developing coun-
not healthy and tries. The globalization trends along with rising standards is creating eating
contributing to patterns that is not healthy and contributing to obesity, diabetes and increased
obesity, diabetes cardiovascular diseases.45 First generation of biotechnology companies success-
and increased fully manufactured recombinant insulin and its varied formulations are now
cardiovascular available in clinical practice. The cure of diabetes by pancreas transplant is
diseases. now an accepted clinical procedure and has success rate of 80-90% in the first
year while by five year it declines to 57%.46 A successful cure of diabetes and
proof of concept was provided for this method in 1993 by using biocompat-
ible membrane that is substantially free from endotoxin content.47 Current
methods to cure of diabetes require that biocompatible material used to
encapsulate insulin producing cells must be substantially free from endotoxin
content. Advances in immunology are leading to the better understandings of
the immune rejection process. In spite of these advances, the currently prac-
ticed technology for the cure of diabetes has many flows and requires further
improvements. In 400 plus patients transplanted the success rate of cure of
diabetes drops from 50% in first year to 33% by third year and to less than
10% by 5th year. Insulin producing cells get immune rejected. Prior to the year
2000 the yield of insulin producing cells was less than 10 % per pancreas and
required as much as 5.6 pancreas to cure one patient with Type 1 Diabetes.
By 2006, the technology has been improved, reducing the need for pancreas
from 5.8 to one.48 A further technology advancement involving stem cells to
manufacture insulin producing cells will outdate the need for donor pancreas
in next few years.49 Such an advance will allow one to cure Type 1 diabetes
at an earlier stage and in a broader level. It is estimated that in the USA total
supply of pancreas is 6000 per year. Since, the cure of diabetes by single

584


pancreas in 2006, is reported, it is expected that number of islet cell transplant
will rise dramatically in coming decade. Economics of each cure of diabetes
cost approximately US$150,000/year that has current success rate of 50% at
one year but drops to 10% by 5th year.50 Technology improvements may open
up a huge market opportunity. With organ donation laws in place in India,
where no islet cell transplants are performed, this provides an opportunity to
collaborate and cooperate. The model example could be extended to clinical
trials of other diseases. Collaborative sharing of data and open access to trial
data, will speed the introduction of new biotherapeutics, identify early deadly
complications and adverse effects and provide a mechanism of accelerating the
clearance of regulatory hurdles.
F. Therapy for Renal Diseases:
In 1995, Institute of kidney diseases in Ahmedabad, GS. initiated “Cell
the institute of
Transplant Laboratory for the cure of diabetes.” However, due to difficulties
involved in curing diabetes, they shifted attention to developing stem cell tech- Kidney diseases,
nologies to address immune rejection problems in kidney transplant patients. incidentally
The Institute of Kidney diseases, incidentally is a largest transplantation is a largest
center in Asia offering low cost renal transplants. The key problem identified transplantation
in kidney transplant patients has been the development of memory responses center in Asia
leading to immune rejection and inadequate response to immune suppressive offering low cost
drugs. The Institute of Kidney Diseases has shown their stem cell technology renal transplants.
advances and how CD 34 cells from donor bone marrow could be transplanted
into recipient patients.51 This procedure helped to reduce cost and effec-
tively reduced the need for immune rejection drugs leading to the successful
outcome in transplanted patients. Many of the transplanted patients however,
were related donors where immune system responses are likely to be weaker.
The institute presented several cases of renal diseases as a part of continuing
medical education. New advances in the fundamentals of immunology have
thrown new lights on the cause and occurrences of adverse effects. This will
lead to better safe immune suppressive drugs with least adverse effects.52
G. Cancer Metastasis:
The human immune system is designed to defeat disease and has the ability
to combat cancer cells. Recent advances of immunology explain and provide
new insight into how cancer cells evade immune responses.53 A large number
of cancers such as breast, bladder, cervix, lung, prostate, ovarian, tropho-
blastic tumors, and thyroid and glioblastoma multiformes are identified that
secrete Factor H or pirate its functioning.54-57) The piracy of Factor H allows
cancer cells to protect against complement mediated formation of Membrane
Attack Complex (MAC). Cancer cells may either prevent the formation of C3
convertase or inactivate MAC on its surface. Therapeutic implications are that
incorporation of Factor H modulator can be exploited strategically to generate
vaccine responses in cancers or to provide immunotherapy.

585


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