Pharmaceutical biotechnology Monoclonal antibodies: boundless ...

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Pharmaceutical biotechnology
Monoclonal antibodies: boundless potential, daunting challenges
Editorial overview
Theodore J Torphy
Current Opinion in Biotechnology 2002, 13:589–591
0958-1669/02/$ - see front matter
© 2002 Elsevier Science Ltd. All rights reserved
Theodore J Torphy Monoclonal antibodies (mAbs) have come of age as therapeutics. A strong
argument can be made that mAbs are responsible for several of the most
Centocor, Inc. 200 Great Valley Parkway Malvern,
important advances in pharmacotherapy over the past decade. Agents such as
PA 19355-1307, USA;
® ® ®
Synagis (palivizumab), Herceptin (trastuzumab) and REMICADE (inflix-
e-mail: ttorphy@cntus.jnj.com
imab) have transformed the treatment of infectious diseases, cancer and
Ted Torphy is Senior Vice President
autoimmune diseases, respectively. Moreover, development pipelines are
of Discovery and Preclinical
bulging with new opportunities. But, like adolescence, the maturing of mAb
Development at Centocor, a
technology into a mainstream therapeutic platform is a turbulent time, one
biopharmaceutical company
that is as fraught with uncertainty as it is with bravado. Simply put, mAbs are
committed to the discovery,
extremely expensive to manufacture and thus costly to patients and health
development, manufacture and
care systems. Much of the expense is associated with the huge capital invest-
commercialization of monoclonal
ment needed to build protein manufacturing facilities. Depending on their
antibodies. His interests include
capacity, these facilities cost between $200 million and $1 billion. Moreover,
technology platforms for the discovery
the commitment to build such a facility must be made four to six years in
of novel drug targets, the creation and
advance if it is to be completed in time to support the launch of a new product.
development of novel protein
Put another way, this commitment must occur before a development candidate
therapeutics, and risk-benefit analysis
is in phase II clinical trials. The risk associated with this capital investment is
of R&D portfolios.
so daunting that, understandably, many companies with promising mAbs in
the pipeline have balked. As a result the industry could witness a threefold
shortfall in manufacturing capacity over the next five years. This dearth of
capacity will place additional pressure on the cost of mAbs.
This volume of Current Opinion in Biotechnology provides an up-to-date
overview of the technologies used to discover and optimize new therapeutic
mAbs, the application of mAbs to three specific therapeutic areas (oncology,
immune-mediated inflammatory diseases and infectious diseases), and the
implementation of new manufacturing technologies. Woven throughout these
reviews is the common theme of a technology platform in transition from
promising concept to tangible reality.
®
In 1986 Orthoclone (muromonab; OKT3) became the first mAb approved
for clinical use. Although this product proved the viability of mAbs as thera-
peutics, it was derived from a murine source. Consequently, Orthoclone’s use
is limited by its immunogenic nature. In the 1990s new technologies, including
the engineering of mouse–human chimeric antibodies and the ‘humanization’
of murine antibodies, greatly reduced, but did not eliminate problems
with immunogenicity. The first two reviews describe state-of-the-art
technologies for creating fully human mAbs, an approach that should further
reduce the immunogenic potential of mAbs. Kellermann and Green
(pp 593–597) discuss the history and continued evolution of transgenic mice
for generating therapeutic mAbs. Inserting transgenes containing large human
immunoglobulin (Ig) loci into a mouse germline creates transgenic mice
capable of generating fully human antibodies when challenged with an
antigen. A number of mAbs derived from transgenic technology are now in
clinical development, and the question of decreased immunogenicity should
soon be answered.590 Pharmaceutical biotechnology
In the second review covering the creation of fully human oncology, immune-mediated inflammatory diseases and
mAbs, Kretzschmar and von Rüden (pp 598–602) focus on infectious diseases. Nakada and colleagues (pp 609–614)
phage display. Compared with transgenic mice, phage delve into the burgeoning field of mAbs as anticancer
display is a fundamentally different concept in identifying therapeutics. Five mAbs are currently licensed in the
mAbs. Whereas the creation of human mAbs in transgenic United States for cancer indications, with many more in
mice relies on the mouse’s natural immune system to respond phase III clinical trials. As pointed out in this review, most
to a foreign protein, phage display is a selection technology in ‘naked’ mAbs (i.e. mAbs that are not conjugated with a
which the desired mAb presumably exists in a pre-made radionuclide or a toxin) are only modestly effective against
10 11 ®
library of 10 –10 distinct mAb fragments. These libraries solid tumors. The one exception to this is Herceptin
are either created recombinantly from a natural human B-cell (trasluzumab), which targets the HER-2 growth factor
®
repertoire or, as in the case of the HuCAL library described receptor and is used in the treatment of metastatic breast
in this review, created modularly by synthesizing cassettes of cancer. Regardless, it is clear that application of the new
all six complementarity determining regions (CDRs) that can molecular technologies to optimize mAbs directed against
then be inserted into human Ig frameworks. One theoretical tumor antigens will be of great utility in improving the
advantage of the phage approach to mAb discovery is that efficacy of antitumor therapeutics. These approaches include
once a lead candidate is identified though screening, its bind- increasing effector function to improve antibody-dependent
ing characteristics can be changed by iteratively inserting new cellular cytotoxicity and complement-dependent cytotoxi-
sequences into any one or all of the six CDRs. This process, city, conjugating mAbs with cytotoxins or radionuclides,
called affinity maturation, can be used to create mAbs with targeting the products toward tumors using immunoliposome
extraordinarily high affinities for their target antigens. This technology and, as discussed in Batra’s review, refining the
approach is analogous to the way in which medicinal chemists macromolecular structure of the mAb to maximize tumor
change the chemical characteristics of a lead pharmacophore penetration. Perhaps nowhere will the impact of evolving
to optimize a therapeutic candidate. In concept, improving mAb optimization technologies be greater than in the
the affinity of mAbs could, under the right circumstances, oncology arena.
reduce the dosage needed for therapeutic benefit. If true,
such an approach could have a positive impact on the cost of The power of mAbs in dissecting the pathophysiology of
mAb therapy. complex, multifactorial immune-mediated inflammatory
diseases is powerfully illustrated by the story of REMI-
®
The molecular form in which mAbs are delivered has an CADE (infliximab), an anti-TNFα mAb. As described by
enormous impact on the therapeutic efficacy of these Andreakos, Taylor and Feldmann (pp 615–620), targeting a
agents. Batra and colleagues (pp 603–608) review the single cytokine, TNFα, with infliximab has outstanding
unique pharmacokinetics and biodistribution of mAbs and efficacy in Crohn’s disease and rheumatoid arthritis. This
mAb fragments. Changing the standard IgG framework not outcome is particularly notable because many would not
only affects the pharmacokinetics of mAbs, it affects the have predicted a positive outcome by inhibiting a single
ability of these agents to penetrate specific tissues. Thus, cytokine in the multifarious bouillabaisse of inflammatory
the therapeutic profile of a mAb can be modified not just by mediators associated with these diseases. Clearly, however,
changing its affinity or selectivity, but also by modulating its the marked efficacy of anti-TNFα mAbs in Crohn’s disease
molecular form to best target the unique pathophysiology of and rheumatoid arthritis tells us that even in immune
different diseases. The most striking example of where disorders in which many mediators are implicated, a small
altering the form of a mAb from the standard IgG format is number might reign supreme. Moreover, in animal models
critically important is in radioimmunotherapy of tumors of a variety of immune-mediated inflammatory diseases,
using radionuclide–mAb conjugates that are targeted for anti-TNFα mAbs as well as mAbs directed against other
specific tumor cell surface markers. Here, the use of IgG cytokines (e.g. IL-1, IL-6), adhesion molecules (e.g. ICAM-1)
radioconjugates is associated with poor tumor penetration, or T-cell antigens (e.g. CD3, CD4, CD5, CD7) often have
high levels of nonspecific binding, and a prolonged plasma similar therapeutic effects. This suggests that immune-
half-life. Obviously, these are not ideal characteristics of a mediated inflammatory diseases as diverse as rheumatoid
molecule that is intended to deliver a lethal radiological arthritis, psoriasis and type I diabetes may share similar
payload specifically to neoplastic cells. On the other hand, molecular and cellular pathophysiologies. Despite the
multivalent single-chain variable fragments of the same optimistic outlook for the use of mAbs in treating immune-
mAb are taken up by tumors to a much greater extent than mediated inflammatory diseases, these authors conclude
the parent IgG, and are associated with much lower non- their review with the caveat that the ultimate success of
specific tissue localization. This review provides a number new mAbs will partly depend on pharmacoeconomic
of examples of how changing the molecular form of a mAb issues. Again, the cost of mAb therapy could limit its wide-
allows one to customize its pharmacokinetic and biodistrib- spread use where more cost-effective therapies are available.
ution characteristics to optimize therapeutic activity.
The third review of therapeutic mAbs by Haslin and
The next three articles deal with the application of mAbs Chermann (pp 621–624) recounts the fascinating story of
to the treatment of diseases in three therapeutic areas: how a unique HIV-associated epitope, R7V, was identifiedEditorial overview Torphy 591
on the surface of HIV-infected cells. This epitope is of plants, most frequently in tobacco or corn. To circumvent
responsible for the generation of protective antibodies in one of the perceived shortcomings of plant-derived mAbs,
HIV-positive individuals who do not progress to AIDS. new technology is being evaluated that allows genes that
Anti-R7V antibodies isolated from non-progressors also support mammalian glycosylation to be inserted into the
neutralize HIV escape mutants from frontline pharmaco- plant genome. In addition to reduced cost of production, the
therapy regimens. By applying contemporary technologies to manufacture of mAbs generated in either transgenic animals
discover and optimize high-affinity anti-R7V mAbs, this or plants has the advantage of being scaled up relatively
story of scientific sleuthing could lead to a new class of quickly without having to make huge capital investments.
anti-HIV therapeutics.
Quite rightly, there is optimism regarding the use of
In a sense, all of the advances in mAb creation and opti- transgenic technology to drive down the cost of mAbs.
mization, as well as the vast therapeutic potential of these While warranted, this optimism is tempered by two facts.
agents, are made irrelevant if the demand for these products First, to date no regulatory authority has licensed a mAb
cannot be met or if they are too costly for health care manufactured from a transgenic source. Second, the huge
systems. The final two articles of this volume describe new advantage promised by transgenic technology is capital
platforms for mAb manufacture that eliminate costly mam- avoidance. That is, there will be a reduced need to invest
malian cell expression technology. Houdebine (pp 625–629) in massively expensive production facilities. Although
provides an overview on the production of mAbs from trans- transgenic technology is likely to reduce the investment
genic animals. This technology takes advantage of inserting needed to generate bulk, unpurified product, a substantial
a gene expressing a specific therapeutic mAb of interest into portion of the cost of mAbs is associated with downstream
the genome of a mammal, a cow or goat for example, such purification and processing. Consequently, the magnitude
that the product is secreted into the animal’s milk. The of the impact that transgenic mAb generation will have on
recombinant mAb is then captured and purified. In addition overall capital investment remains unclear.
to the purported cost advantage of this approach over
mammalian cell culture technology, mAbs made in trans- Undeniably, enormous strides have been made in the past
genic animals will have glycosylation patterns more similar decade with respect to mAb discovery, optimization and
to those found in human mAbs than in those derived from therapeutics. The stark reality remains, however, that
plants. This glycosylation pattern may be important for unless the industry succeeds in bringing down the cost of
immunogenicity as well as for effector functions such as therapy, mAbs will never reach their full commercial or
antibody-dependent cellular cytotoxicity. Hood and medical potential. This is a battle that is just beginning to
colleagues (pp 630–635) review the state of mAb production be waged. Janus, the double-faced Roman god of the past
in transgenic plants. mAbs have been produced by a variety and future, would be keenly interested in its outcome.