CDC-NII Malaria Vaccine. Tools
of cell biology and genetic engineering are being used
for replacing existing vaccines, with safer and more
effective versions and are improving the prospects of
new vaccines against AIDS, cancer, malaria and other
parasitic infections. For instance, Dr Hasnain at NII
has made a composite gene by stitching together
several gene fragments for proteins exprissed in
various stages of malaria parasite's development, and
expressed this engineered gene in baculoviruses.
Studies at CDC with this artificial protein look
highly promising as a new lead towards a candidate
vaccine against malaria.
Towards the medicines of
tomorrow: targeted drugs. Despite such welcome
developments, the fact is that effective treatments
against new and re-emerging diseases are proving ever
harder to invent. New drugs becoming increasingly
difficult to come by, we Sought alternative means so
that molecules with desired curative potential that
are currently unusable due to toxic side effects can
be made therapeutically useful. Let me illustrate our
approach towards such medicines of tomorrow.
Advantages of Site specific drug
delivery. Why drugs often produce toxic reactions?
Current pharmacological practice is based on the
central dogma that the .effect of a drug depends on
its concentration in the blood or other body fluids.
Of about 1013 cells comprising the human body, only a
small fraction needs intervention with drugs to cure
or curb a specific disease, Having no special affinity
for the diseased target cells, most drugs in current
use can access normal cells as well. Since most drugs
enter cells by passive diffusion, a relativelyhigh
dose of the drug needs to be administered to attain
therapeutically effective drug concentration inside.
the cells, which aggravates the problem of toxicity.
Ever since Paul Ehrlich introduced the concept of
magic bullets in 1906, a common priority goal of
therapeutics has been the designing of vehicles
containing exclusive signals for recognizing the
target cells, and delivering drugs selectively to
Targets on cell surface. Two
general targets on the surface of mammalian cells are
exploitable for such site-specific drug delivery: 1)
antigens against which specific, non-cross-reactive
antibodies can be developed, and 2)receptor molecules
capable of efficient transport of macromolecular
ligands. The carrier for targeting a drug to specific
cells thus can either be an antibody specific for the
target cell, or a ligand for the receptor molecules
present only on the target cells (Basu 1990). Ehrlich
himself proposed the use of a specific antibody as the
carrier of the chemotherapeutic agent.
Disadvantages of Anti body-med iated targeting: The
antibody-mediated targeting approachr raised great
hopes after fine discovery of hybridorna technology
for production of highly specific monoclonal
antibodies. However, it has still not been possible to
solve many of the problems of this approach.
Receptor-tirtediated transport of LDL. The
receptor-mediated approach is of more recent vintage
and derives from our work on the role of low-density
lipoprotein in atherosclerosis. This work delineated
how specific receptor molecules on the surface of
rnammalian cells bind macromolecules, leading to their
internalisation and processing in specific
intracellular compartments. This process is now called
receptor-mediated endocytosis and is universally
recognised as a major transport mechanism utilised by
mammalian cells for a variety of purposes.
LDL receptor work established. We had great fun
working out the mysteries of this process during
1975-83 but the story is textbook matter now.
Characteristics of Receptor-mediated
endocytosis important for drug delivery. Twenty years
ago, thanks to late Professor B.K Bachhawat, I got a
job in India. Not having much of a lab to begin with,
I had all the time to ponder over how to build a
scientific career in India. There was no point working
on LDL as my seniors in the LDL receptor adventure,
Goldstein and Brown, were already on the verge of a
Nobel Prize which came in 1985. Eventually I realized
the potential of the process of receptor-mediated
endocytosis for the purposes of drug delivery.
Macrophages pivotal cells. I
also understood that macrophages in animals mount
multipronged defensive responses that protect them
against a variety of invading microorganisms and
developing cancers. However, in many instances these
defensive responses are overwhelmed, circumvented or
even misdirected so that these protective cells become
the focal points in a large number of diseases -
infectious, metabolic or neoplastic, which affect
millions of people world wide. Therefore, a
generalised targeting regimen specific for macrophages
would be extremely useful.
Characteristics of Scavenger
receptor system: To target macrophages we needed a
receptor restricted to these cells. In the course of
my earlier work on lipoprotein metabolism we
discovered a receptor system present primarily on
cells of marophage lineage. It appears that God
created scavenger receptors for my career development
Pathway of receptor-mediated
drug delivery. We went about exploiting the principles
of receptor-mediated endocytosis for selective drug
delivery. We chemically attached the desired molecule
to maleylated albumin or polyguanylic acid so that the
conjugate is specifically recognized by the scavenger
receptors present primarily on macrophages.