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‘Our
focus would be on partnerships to commercialize promising biomedical
leads’
 Padma
Shree Dr Sandip Basu, director, National Institute of Immunology
(NII), who pioneered the concept of receptor-mediated targeting
of drugs, has made significant contributions in India and abroad
in the areas of selective drug delivery, regulation of cholesterol
metabolism and microbial genetics. Dr Basu, the prime figure in
nurturing NII and IMTECH, speaks with Jayashree Padmini on
biotech research in India
Your
new therapeutic approach of receptor-mediated targeting of drugs
against macrophage associated infections like Kala Azar, TB &
cancer has won accolades. Can you elaborate on this concept?
The concept was developed basically recognizing the fact that in
the existing methodologies of drug delivery the risk of exposure
of healthy cells to serious adverse reactions. The idea was to formulate
new modalities of delivering the drug molecules primarily to the
target cells and/or intracellular sites at relatively low extra
cellular concentrations that ensure reduced drug uptake by non-target
cells to minimize such side effects. Site-specific drug delivery
is still in the experimental stage and the approach is to attach
the therapeutic agent to a carrier recognized only by the cells
where pharmacological action needed. Antigens capable of generating
specific, non-crossreactive antibody and receptors on the cell surface
capable of efficient transport of the ligands come in handy as recognition
elements. However, incomplete specificity for the target cells and
poor internalization of antibody-drug conjugates still limit the
usefulness of antibodies for site-specific drug delivery applications
necessitating exploration of alternatives. Since macrophage-associated
disorders affect millions of people the world over as well as in
India, we sought to develop a new strategy for targeting of therapeutic
agents to macrophages without the limitations of the current approaches
using antibodies and liposomes. Our approach is to work out a strategy
of intervening in macrophage-associated disease processes through
modification or manipulation of macrophage metabolism. The methodology
was exploiting the exquisite cell-type specificity and high efficiency
of endocytosis of macromolecules mediated by the scavenger receptors
for intracellular delivery of pharmacologically active agents selectively
to these cells. Site-specificity is conferred on an appropriate
molecule by conjugating it through chemical methods to a macromolecular
ligand (e.g., maleylated albumin or polyguanylic acid) specifically
recognized by the scavenger receptors present primarily on cells
of macrophage lineage.
Could
you brief us on the work undertaken for site specific drug delivery?
We demonstrated for the first time that a drug molecule can be targeted
selectively to macrophages by attaching it to a macromolecular carrier
specifically recognized by the scavenger receptors present principally
on macrophages (1989). We found that drug-carrier complexes bound
to these receptors are rapidly internalized by macrophages where
the carrier portion of the conjugate is degraded leading to efficient
intracellular release of the drug. The versatility and superior
efficacy of this novel approach was shown in model systems of leishmaniasis,
tuberculosis, antisense therapy of viral infections, histiocytic
malignancy and multidrug resistant cancer (1995), in which macrophages
are affected. Receptor-mediated interventions in macrophage metabolism
were also exploited in collaboration with Dr Rath’s group at
NII to modulate immune responses which established that targeting
antigens to scavenger receptors enhances immunogenicity of antigens
indicating a new design principle for generating adjuvantless vaccines,
generates the Th1 type of immune response ushering in a new approach
for immunoprophylaxis especially against intracellular infections,
diverts an ongoing allergic immune response to a non-allergic route
brightening the prospect of mitigating the misery of suffering millions
and abrogates T cell tolerance to self-antigens providing a new
tool to dissect mechanisms of immune tolerance and etiopathogenesis
of autoimmune diseases. Furthermore, we recently reported the discovery
of a new receptor system that mediates uptake and intracellular
degradation of haemoglobin by the intracellular parasite Leishm-ania,
which elucidated how this parasite, which lacks haeme biosynthetic
ability, meets the requirement of haeme essential for its growth
and suggests new targets for therapeutic interventions, and the
molecular mechanism the intracellular pathogen Salmon-ella use to
survive within macrophages in collaboration with Dr Mukhopad-hyay’s
group at NII. The works done in the country has been outlined in
22 research articles in internationally acclaimed scientific journals
and has received five national and international patents. This provides
a new and general principle for cure and prevention of the whole
spectrum of macrop-hage-associated disorders which include infectious,
metabolic, and neoplastic diseases affecting millions of people
especially in the Third World as well as provides new insights into
the mechanisms of intracellular parasitism.
NII
which has a mandate of research on immunological defense mechanisms
has to take a proactive role in developing methodologies that are
capable of addressing the health concerns of the country, particularly
in the era of fast changing pharmacology and business equations.
What is the institute’s strategy?
In
view of the unprecedented explosion in biotechnological advances
worldwide, NII is focussing its efforts on creating the scientific
base for innovations of relevance to the healthcare delivery systems
in India. The future mandate would revolve around developing new
research leads for health care systems and designing novel approaches
that would create new directions for industrial exploitation in
the global market place.
NII
would position itself as a premium institute with stress on research
of such excellence as to provide novel ways of preventing and treating
diseases, that would range from innovative technological issues
such as tissue engineering, novel delivery systems, novel immunomodulatory
lead structures or immunosensors to fundamental immunobiological
investigations in pathophysiological mechanisms. NII will make certain
that the benefits of such research for the country is maximized
by ensuring that international patent protection is obtained for
all such discoveries.
How
do you address the issue of translating the research results to
the benefits of common man?
Apart
from presenting well formulated research papers our focus would
be directed to industrial partnerships to commercialize all promising
leads with the potential of biomedical applications so that the
health concerns of the common man is well addressed. Further, NII
is proposing a new modality for enhancing the international competitiveness
of indigenous industry in medical biotechnology. Here, the institute
enters into collaborations with Indian industries by providing them
with incubator laboratory facilities and intellectual resources
in addition to transferring the seed discoveries that NII has made
in the interim. This would provide the closest Indian industry-academia
interface yet in medical biotechnology, and would ensure that industries
have a realistic chance of assimilating the advances generated at
NII.
Could
you give us an idea on the nature of the work undertaken in US and
its significance?
During
1975-84, the research team including me was working in the area
of regulation of cholesterol metabolism in mammalian cells in the
US. This work provided the rationale for new generation cholesterol-lowering
agents [the statins], pre-natal diagnosis of familial hypercholesterolemia,
and recently, the gene therapy of familial hypercholesterolemia.
This work has brought 1985 Nobel Prize in Medicine to the team leaders
MS Brown and JL Goldstein.
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