Proteins have the most dynamic and diverse
role of any macromolecule in the body,
catalysing biochemical reactions, forming
receptors and channels in membranes, pro-
viding intracellular and extracellular
scaffolding support, and transporting
molecules within a cell or from one organ to
another. It is currently estimated that there are
25,000–40,000 different genes in the human
genome, and with alternative splicing of
genes and post-translational modification of
proteins (for example, by cleavage, phosphory-
lation, acylation and glycosylation), the
number of functionally distinct proteins is
likely to be much higher1–3. Viewed from the
perspective of disease mechanisms, these esti-
mates pose an immense challenge to modern
medicine, as disease may result when any one
of these proteins contains mutations or other
abnormalities, or is present in an abnormally
high or low concentration. Viewed from the
perspective of therapeutics, however, these
estimates represent a tremendous opportunity
in terms of harnessing protein therapeutics
to alleviate disease. At present, more than
130 different proteins or peptides are
approved for clinical use by the US Food
and Drug Administration (FDA), and many
more are in development.
Protein therapeutics have several
advantages over small-molecule drugs.
First, proteins often serve a highly specific
and complex set of functions that cannot be
mimicked by simple chemical compounds.
Second, because the action of proteins is
highly specific, there is often less potential for
protein therapeutics to interfere with normal
biological processes and cause adverse effects.
Third, because the body naturally produces
many of the proteins that are used as thera-
peutics, these agents are often well tolerated
and are less likely to elicit immune responses.
Fourth, for diseases in which a gene is
mutated or deleted, protein therapeutics
can provide effective replacement treatment
without the need for gene therapy, which
is not currently available for most genetic
disorders. Fifth, the clinical development and
FDA approval time of protein therapeutics
may be faster than that of small-molecule
drugs. A study published in 2003 showed
that the average clinical development and
approval time was more than 1 year faster for
33 protein therapeutics approved between
1980 and 2002 than for 294 small-molecule
drugs approved during the same time period4.
Last, because proteins are unique in form
and function, companies are able to obtain
far-reaching patent protection for protein
therapeutics. The last two advantages make
proteins attractive from a financial perspec-
tive compared with small-molecule drugs.
A relatively small number of protein
therapeutics are purified from their native
source, such as pancreatic enzymes from
hog and pig pancreas5,6, and α-1-proteinase
inhibitor from pooled human plasma7,8,
but most are now produced by recombinant
DNA technology and purified from a wide
range of organisms. Production systems
for recombinant proteins include bacteria,
yeast, insect cells, mammalian cells, and
transgenic animals and plants9–13. The
system of choice can be dictated by the cost
of production or the modifications of the
protein (for example, glycosylation, phos-
phorylation or proteolytic cleavage) that are
required for biological activity. For example,
bacteria do not perform glycosylation
reactions, and each of the other biological
systems listed above produces a different
type or pattern of glycosylation. Protein
glycosylation patterns can have a dramatic
effect on the activity, half-life and immuno-
genicity of the recombinant protein in the
body. For example, the half-life of native
erythropoietin, a growth factor important in
erythrocyte production (see below), can be
lengthened by increasing the glycosylation
of the protein. Darbepoetin-α is an erythro-
poietin analogue that is engineered to
contain two additional amino acids that are
substrates for N-linked glycosylation reac-
tions. When expressed in Chinese hamster
ovary cells, the analogue is synthesized with
five rather than three N-linked carbohydrate
chains; this modification causes the half-life
of darbepoetin to be threefold longer than
that of erythropoietin14.
Perhaps the best example of trends in the
production and use of protein therapeutics
is provided by the history of insulin in the
treatment of diabetes mellitus type I (DM-I)
and type II (DM-II). Untreated, DM-I is
a disease that leads to severe wasting and
death due to lack of the protein hormone
insulin, which signals cells to perform
numerous functions related to glucose
homeostasis and intermediary metabo-
lism15. In 1922, insulin was first purified
from bovine and porcine pancreas and used
as a life-saving daily injection for patients
with DM-I16. At least three problems
hindered the widespread use of this protein
therapy: first, the availability of animal pan-
creases for purification of insulin; second,
the cost of insulin purification from animal
A guide to drug discovery — opinion
Protein therapeutics: a summary
and pharmacological classification
Benjamin Leader, Quentin J. Baca and David E. Golan
Abstract | Once a rarely used subset of medical treatments, protein therapeutics
have increased dramatically in number and frequency of use since the introduction
of the first recombinant protein therapeutic — human insulin — 25 years ago.
Protein therapeutics already have a significant role in almost every field of
medicine, but this role is still only in its infancy. This article overviews some of the
key characteristics of protein therapeutics, summarizes the more than 130 protein
therapeutics used currently and suggests a new classification of these proteins
according to their pharmacological action.
NATUre reVIeWS | drug discovery
VoLUMe 7 | jANUAry 2008 | 21
© 2008 Nature Publishing Group
pancreas; and third, the immunological
reaction of some patients to animal insulin.
These problems were addressed by isolating
the human insulin gene and engineering
Escherichia coli to express human insulin
by using recombinant DNA technology.
By growing vast quantities of these bacteria,
large-scale production of human insulin was
achieved. The resulting insulin was abun-
dant, inexpensive, of low immunogenicity
and free from other animal pancreatic
substances. recombinant insulin, approved
by the US FDA in 1982, was the first
commercially available recombinant protein
therapeutic, and has been the major therapy
for DM-I (and a major therapy for DM-II)
recombinantly produced proteins can
have several further benefits compared with
non-recombinant proteins. First, transcrip-
tion and translation of an exact human gene
can lead to a higher specific activity of the
protein and a decreased chance of immuno-
logical rejection. Second, recombinant pro-
teins are often produced more efficiently and
inexpensively, and in potentially limitless
quantity. one striking example is found in
the protein-based therapy for Gaucher’s
disease, a chronic congenital disorder of
lipid metabolism caused by a deficiency
of the enzyme β-glucocerebrosidase (also
known as glucosylceramidase) that is char-
acterized by an enlarged liver and spleen,
increased skin pigmentation and painful
bone lesions21,22. At first, β-glucocerebro-
sidase purified from human placenta was
used to treat this disease, but this requires
purification of protein from 50,000 placentas
per patient per year, which obviously places
a practical limit on the amount of purified
protein available. A recombinant form of
β-glucocerebrosidase was subsequently
developed and introduced, which is not
only available in sufficient quantities to treat
many more patients with the disease, but
also eliminates the risk of transmissible
(for example, viral or prion) diseases associ-
ated with purifying the protein from human
placentas23–25. This also illustrates a third
benefit of recombinant proteins over non-
recombinant proteins — the reduction of
exposure to animal or human diseases.
A fourth advantage is that recombinant
technology allows the modification of a
protein or the selection of a particular gene
variant to improve function or specificity.
Again, recombinant β-glucocerebrosidase
provides an interesting example. When this
protein is made recombinantly, a change
of amino-acid arginine-495 to histidine
allows the addition of mannose residues
to the protein. The mannose is recognized
by endocytic carbohydrate receptors on
macrophages and many other cell types,
allowing the enzyme to enter these cells
more efficiently and to cleave the intracellu-
lar lipid that has accumulated in pathological
amounts, which results in an improved
therapeutic outcome23. Last, recombinant
technology allows the production of proteins
that provide a novel function or activity,
as discussed below.
The 25 years since the approval of
recombinant insulin by the FDA have seen a
remarkable expansion in the number of thera-
peutic applications of proteins. More than
130 proteins (over 95 of which are produced
recombinantly) are currently approved for
clinical use by the FDA, and many more
are in development. An appreciation of the
many therapeutic uses of proteins may be
facilitated by categorizing such therapies
according to their mechanism of action,
and, in this article, we summarize currently
approved protein therapeutics by suggesting
a classification system that is based on their
pharmacological action (BOX 1). examples
Box 1 | Functional classification of protein therapeutics
Protein therapeutics in the tables in this article are organized by function and therapeutic
application. The numbers of therapeutics per group reflect the relative difficulty associated with
drug development across the various classes of protein therapeutics. Every effort has been made to
include in these tables all US Food and Drug Administration (FDA)-approved Group I and Group II
protein-based therapies. Groups III and IV present selected examples that highlight the use of
proteins in vaccines and diagnostic agents.
group i: protein therapeutics with enzymatic or regulatory activity
• Ia: Replacing a protein that is deficient or abnormal (TABLES 1,2).
• Ib: Augmenting an existing pathway (TABLES 3,4).
• Ic: Providing a novel function or activity (TABLE 5).
Endocrine and metabolic disorders with defined molecular aetiologies dominate Group Ia. As more
diseases are linked to deficiencies of specific proteins, this class will continue to grow. Group Ib is
dominated by therapies that augment haematological and endocrine pathways and immune
responses. The many interferon and growth factor therapies in Group Ib effectively treat disease
even when their precise pharmacological mechanism of action is unknown. Group Ic demonstrates
the rational use of naturally occurring proteins to modify the pathophysiology of human diseases.
The future growth of this class depends on understanding protein function in human physiology as
well as protein function in other organisms.
group ii: protein therapeutics with special targeting activity
• IIa: Interfering with a molecule or organism (TABLES 6,7).
• IIb: Delivering other compounds or proteins (TABLE 8).
Group IIa therapeutics use their special targeting activity to interfere with molecules or organisms
by binding specifically to them and blocking their function, targeting them for destruction,
or stimulating a signalling pathway. This group has grown as monoclonal antibody technology has
matured and will probably expand further as signalling pathways and aetiologies of disease are more
clearly identified. Group IIb therapeutics deliver other compounds or proteins to a specific site.
This class has great potential to grow, as demonstrated by the breadth of the specifically targeted
Group IIa therapies.
group iii: protein vaccines
• IIIa: Protecting against a deleterious foreign agent.
• IIIb: Treating an autoimmune disease.
• IIIc: Treating cancer.
Although this is currently a small class of therapies, there is great potential for the production of
recombinant vaccines that provide broad protection against infectious agents. Similarly,
individualized vaccines against cancers are likely to be in great demand. Selected examples of the
57 FDA-approved vaccines in TABLE 9 highlight the use of recombinant protein technology in
vaccine production. Many of the FDA-approved vaccines protect against multiple infectious
agents and include synthetic, recombinant and purified protein components. A complete list of
FDA-approved vaccines may be found at: http://www.fda.gov/cber/vaccine/licvacc.htm.
group iv: protein diagnostics
Group IV protein diagnostics, for which selected examples are shown in TABLE 10, are a class that
powerfully affect clinical decision-making. These diagnostics use technology and therapeutics
developed in other classes to answer clinical questions. This table presents primarily in vivo protein
diagnostics, but in vitro protein diagnostics are also critical to medical decision-making and are too
numerous to address comprehensively here.
22 | jANUAry 2008 | VoLUMe 7
© 2008 Nature Publishing Group
of protein therapeutics in each category and
clinical conditions in which they are used
are discussed in the text, and a listing of
FDA-approved protein therapies and their
functions and clinical uses is presented
in TABLES 1–8. examples of protein-based
vaccines and diagnostics that highlight the
growing importance of proteins in medicine
are provided in TABLES 9,10.
group i: enzymes and regulatory proteins
Protein therapeutics in this group function
by a classic paradigm in which a specific
endogenous protein is deficient, and the
deficit is then remedied by treatment with
exogenous protein. Protein therapeutics
that we have classified in Group Ia are used
to replace a particular activity in cases of
protein deficiency or abnormal protein
production. These proteins are used in a
range of conditions, from providing lactase
in patients lacking this gastrointestinal
enzyme26 to replacing vital blood-clotting
factors such as factor VIII27,28 and factor
IX29,30 in haemophiliacs. A classic example,
as mentioned above, is the use of insulin
for the treatment of diabetes. Another
important example is in the treatment of
Table 1 | protein therapeutics replacing a protein that is deficient or abnormal (group ia)*
Endocrine disorders (hormone deficiencies)
Trade nameFunction examples of clinical use
regulates blood glucose, shifts potassium into cells Diabetes mellitus, diabetic
exubera insulin formulated for inhalation with faster onset
insulin analogues with faster onset of action and
shorter duration of action
insulin protamine crystalline formulation with slower
onset of action and longer duration of action
insulin analogues with slower onset of action and
longer duration of action
insulin zinc hexameric complex with slower onset
of action and longer duration of action
Mechanism unknown; recombinant synthetic peptide
analogue of human amylin (a naturally occurring
neuroendocrine hormone regulating post-prandial
Anabolic and anticatabolic effector
symlinDiabetes mellitus, in combination
Growth failure due to GH deficiency
or chronic renal insufficiency,
Prader-Willi syndrome, Turner
syndrome, AiDs wasting or cachexia
with antiviral therapy
Growth failure in children with GH
gene deletion or severe primary iGF1
Growth failure in children with GH
gene deletion or severe primary iGF1
recombinant insulin-like growth factor 1 (iGF1) induces
mitogenesis, chondrocyte growth and organ growth,
which combine to restore appropriate statural growth
similar to mecasermin; iGF1 bound to iGF binding
protein 3 (iGFBP3) is thought to keep the hormone
inactive until it reaches its target tissues, thereby
decreasing hypoglycaemia-like side effects
Haemostasis and thrombosis
coagulation factorHaemophilia A
Purified human AT-iii from pooled plasma inactivates
thrombin by forming a covalent bond between the
catalytic serine residue of thrombin and an arginine
reactive site on AT-iii; AT-iii replacement therapy
prevents inappropriate blood-clot formation
After activation by the thrombin–thrombomodulin
complex, protein c inhibits coagulation factors va
Hereditary AT-iii deficiency in
connection with surgical or
obstetrical procedures or for
ceprotin Treatment and prevention of venous
thrombosis and purpura fulminans
in patients with severe hereditary
protein c deficiency
*continued in TABLE 2. Protein therapeutics derive their specificity and function from their structure. Molecules ranging from large and complex enzymes to short peptide
sequences have specific biological activity due to their amino-acid-based secondary and tertiary structure. For example, somatostatin is active as either a 14 or 28 amino-acid
peptide, and its even shorter synthetic analogues share a characteristic hairpin-loop structure that defines their specificity and biological activity. some very short peptide
therapeutics are better thought of as small-molecule drugs, as they lack secondary and tertiary structures that define their biological activity. For this reason, therapeutics such as
glatiramer acetate (a four amino-acid peptide consisting of acetate with l-Glu, l-Ala, l-Tyr and l-Lys) are not addressed in this article. Protein therapeutics are recombinant unless
otherwise stated. ‡Also classed in Group ib. §Non-recombinant.
NATUre reVIeWS | drug discovery
VoLUMe 7 | jANUAry 2008 | 23
© 2008 Nature Publishing Group
97. Shi, L. et al. Gardasil: prophylactic human
papillomavirus vaccine development — from bench
top to bed-side. Clin. Pharm. Ther. 81, 259–264
98. MacKenzie, I. Z. et al. Efficacy and safety of a new,
chromatographically purified rhesus (D)
immunoglobulin. Eur. J. Obstet. Gynecol. Reprod. Biol.
117, 154–161 (2004).
99. McCormick, A. A. et al. Rapid production of specific
vaccines for lymphoma by expression of the tumor-
derived single-chain Fv epitopes in tobacco plants.
Proc. Natl Acad. Sci. USA 96, 703–708 (1999).
100. Campos-Neto, A. et al. Evaluation of DPPD, a single
recombinant Mycobacterium tuberculosis protein as
an alternative antigen for the Mantoux test.
Tuberculosis (Edinb.) 81, 353–358 (2001).
101. Coler, R. N. et al. Cloning of a Mycobacterium
tuberculosis gene encoding a purifed protein derivative
protein that elicits strong tuberculosis-specific delayed-
type hypersensitivity. J. Infect. Dis. 182, 224–233
102. Duchin, J. S., Jereb, J. A., Nolan, C. M., Smith, P. &
Onorato, I. M. Comparison of sensitivities to two
commercially available tuberculin skin test reagents in
persons with recent tuberculosis. Clin. Infect. Dis. 25,
103. Ranke, M. B. et al. Testing with growth hormone-
releasing factor (GRF(1–29)NH2) and
somatomedin C measurements for the evaluation of
growth hormone deficiency. Eur. J. Pediatr. 145,
104. Ghigo, E. et al. New approach to the diagnosis of
growth hormone deficiency in adults. Eur. J. Endocrinol.
134, 352–356 (1996).
105. Ladenson, P. W. et al. Comparison of administration of
recombinant human thyrotropin with withdrawal of
thyroid hormone for radioactive iodine scanning in
patients with thyroid carcinoma. N. Engl. J. Med. 337,
106. Meier, C. A. et al. Diagnostic use of recombinant
human thyrotropin in patients with thyroid carcinoma
(phase I/II study). J. Clin. Endocrinol. Metab. 78,
107. Taillefer, R., Edell, S., Innes, G. & Lister-James, J.
Acute thromboscintigraphy with Tc-99m-apcitide:
results of the phase 3 multicenter clinical trial
comparing Tc-99m-apcitide scintigraphy with contrast
venography for imaging acute DVT. J. Nucl. Med. 41,
108. Sodee, D. B. et al. Multicenter ProstaScint imaging
findings in 2154 patients with prostate cancer.
Urology 56, 988–993 (2000).
109. Urnovitz, H. B., Sturge, J. C. & Gottfried, T. D.
Increased sensitivity of HIV-1 antibody detection.
Nature Med. 3, 1258 (1997).
110. Van de Perre, P. et al. Postnatal transmission of human
immunodeficiency virus type 1 from mother to infant.
A prospective cohort study in Kigali, Rwanda. N. Engl.
J. Med. 325, 593–598 (1991).
111. Busch, M. P. et al. Evaluation of screened blood
donations for human immunodeficiency virus type 1
infection by culture and DNA amplification of pooled
cells. N. Engl. J. Med. 325, 1–5 (1991).
112. Van der Poel, C. L. et al. Confirmation of hepatitis C
virus infection by new four-antigen recombinant
immunoblot assay. Lancet 337, 317–319 (1991).
113. Soffredini, R. et al. Increased detection of antibody to
hepatitis C virus in renal transplant patients by third-
generation assays. Am. J. Kidney Dis. 28, 437–440
114. Putney, S. D. & Burke, P. A. Improving protein
therapeutics with sustained-release formulations.
Nature Biotech. 16, 153–157 (1998).
115. Mahmood, I. & Green, M. D. Pharmacokinetic and
pharmacodynamic considerations in the development
of therapeutic proteins. Clin. Pharmacokinet. 44,
116. Schellekens, H. Bioequivalence and the
immunogenicity of biopharmaceuticals. Nature Rev.
Drug Discov. 1, 457–462 (2002).
117. Peerlinck, K., Arnout, J., Gilles, J. G., Saintremy, J. M.
& Vermylen, J. A higher than expected incidence of
factor-VIII inhibitors in multitransfused hemophilia-A
patients treated with an intermediate purity
pasteurized factor-VIII concentrate. Thromb. Haemost.
69, 115–118 (1993).
118. Gilles, J. G., Arnout, J., Vermylen, J. & Saint-Remy,
J. M. Anti-factor VIII antibodies of hemophiliac patients
are frequently directed towards nonfunctional
determinants and do not exhibit isotypic restriction.
Blood 82, 2452–2461 (1993).
119. Mascelli, M. A. et al. Molecular, biologic, and
pharmacokinetic properties of monoclonal antibodies:
impact of these parameters on early clinical
development. J. Clin. Pharm. 47, 553–565 (2007).
120. Reichert, J. M. & Valge-Archer, V. E. Development
trends for monoclonal antibody cancer therapeutics.
Nature Rev. Drug Discov. 6, 349–356 (2007).
121. Bussel, J. B. et al. AMG 531, a thrombopoiesis-
stimulating protein, for chronic ITP. N. Engl. J. Med.
355, 1672–1681 (2006).
122. Li, J. Z. et al. Thrombocytopenia caused by the
development of antibodies to thrombopoietin. Blood
98, 3241–3248 (2001).
123. Basser, R. L. et al. Development of pancytopenia with
neutralizing antibodies to thrombopoietin after
multicycle chemotherapy supported by megakaryocyte
growth and development factor. Blood 99, 2599–2602
124. Walsh, C. T. Posttranslational Modification of Proteins:
Expanding Nature’s Inventory (Roberts & Company,
125. Frokjaer, S. & Otzen, D. E. Protein drug stability: a
formulation challenge. Nature Rev. Drug Discov. 4,
126. Fowler, S. B. et al. Rational design of aggregation-
resistant bioactive peptides: reengineering human
calcitonin. Proc. Natl Acad. Sci. USA 102,
127. Dinnis, D. M. & James, D. C. Engineering mammalian
cell factories for improved recombinant monoclonal
antibody production: lessons from nature?
Biotechnol. Bioeng. 91, 180–189 (2005).
128. Datar, R. V., Cartwright, T. & Rosen, C. G. Process
economics of animal cell and bacterial fermentations:
a case study analysis of tissue plasminogen activator.
Biotechnology (NY) 11, 349–357 (1993).
129. Lillico, S. G., McGrew, M. J., Sherman, A. &
Sang, H. M. Transgenic chickens as bioreactors for
protein-based drugs. Drug Discov. Today 10, 191–196
130. Pogue, G. P., Lindbo, J. A., Garger, S. J. &
Fitzmaurice, W. P. Making an ally from an enemy:
plant virology and the new agriculture. Annu. Rev.
Phytopathol. 40, 45–74 (2002).
131. Micheletti, M. et al. Fluid mixing in shaken bioreactors:
implications for scale-up predictions for microlitre-scale
microbial and mammalian cell cultures. Chem. Eng. Sci.
132. Gross, M. L. Ethics, policy, and rare genetic disorders:
the case of Gaucher disease in Israel. Theor. Med.
Bioeth. 23, 151–170 (2002).
133. Finkelstein, B. S. et al. Effect of growth hormone
therapy on height in children with idiopathic short
stature: a meta-analysis. Arch. Pediatr. Adolesc. Med.
156, 230–240 (2002).
134. Hokken-Koelega, A. C. et al. Growth hormone
treatment in growth-retarded adolescents after renal
transplant. Lancet 343, 1313–1317 (1994).
135. Howrie, D. L. Growth hormone for the treatment of
growth failure in children. Clin. Pharm. 6, 283–291
136. Salomon, F., Cuneo, R. C., Hesp, R. & Sonksen, P. H.
The effects of treatment with recombinant human
growth hormone on body composition and metabolism
in adults with growth hormone deficiency. N. Engl. J.
Med. 321, 1797–1803 (1989).
137. Thorner, M. O. et al. The diagnosis of growth hormone
deficiency (GHD) in adults. J. Clin. Endocrinol. Metab.
80, 3097–3098 (1995).
138. Graham, J., Muhsin, M. & Kirkpatrick, P. Cetuximab.
Nature Rev. Drug Discov. 3, 549–550 (2004).
139. Goldberg, R. M. & Kirkpatrick, P. Cetuximab. Nature
Rev. Drug Discov. 4 (Suppl. 1) S10–S11 (2005).
140. Saltz, L. B. et al. Phase II trial of cetuximab in patients
with refractory colorectal cancer that expresses the
epidermal growth factor receptor. J. Clin. Oncol. 22,
141. Warrier, I. et al. Factor IX inhibitors and anaphylaxis in
hemophilia B. J. Pediatr. Hematol. Oncol. 19, 23–27
142. Thorland, E. C. et al. Anaphylactic response to factor IX
replacement therapy in haemophilia B patients:
complete gene deletions confer the highest risk.
Haemophilia 5, 101–105 (1999).
143. Rosenberg, R. D., Goldman, P., Bing, D. & Glass, J.
Actions and interactions of antithrombin and heparin.
N. Engl. J. Med. 292, 146–151 (1975).
144. Mannucci, P. M., Boyer, C., Wolf, M., Tripodi, A. &
Larrieu, M. J. Treatment of congenital antithrombin-III
deficiency with concentrates. Br. J. Haematol. 50,
145. Moritz, B. et al. The efficacy and safety of protein C
concentrate (Human) vapor-heated in the treatment of
severe congenital protein C deficiency with or without
pupura fulminans. Blood 96, 53A–53A (2000).
146. Quattrin, T., Belanger, A., Bohannon, N. J. V. &
Schwartz, S. L. Efficacy and safety of inhaled insulin
(Exubera) compared with subcutaneous insulin therapy
in patients with type 1 diabetes — results of a
6-month, randomized, comparative trial. Diabetes
Care 27, 2622–2627 (2004).
147. Hollander, P. A. et al. Efficacy and safety of inhaled
insulin (Exubera) compared with subcutaneous insulin
therapy in patients with type 2 diabetes — results of a
6-month, randomized, comparative trial. Diabetes
Care 27, 2356–2362 (2004).
148. Skyler, J. S. et al. Efficacy of inhaled human insulin in
type 1 diabetes mellitus: a randomised
proof-of-concept study. Lancet 357, 331–335 (2001).
149. Edwards, D. A. et al. Large porous particles for
pulmonary drug delivery. Science 276, 1868–1871
150. Hirsch, I. B. Drug therapy: Insulin analogues. N. Engl. J.
Med. 352, 174–183 (2005).
151. Dreyer, M. et al. Efficacy and safety of insulin glulisine
in patients with type 1 diabetes. Horm. Metab. Res.
37, 702–707 (2005).
152. Soran, H. & Younis, N. Insulin detemir: a new basal
insulin analogue. Diabetes Obes. Metab. 8, 26–30
153. Thompson, R. G., Peterson, J., Gottlieb, A. & Mullane,
J. Effects of pramlintide, an analog of human amylin,
on plasma glucose profiles in patients with IDDM —
results of a multicenter trial. Diabetes 46, 632–636
154. Backeljauw, P. F. & Underwood, L. E. Therapy for
6.5–7.5 years with recombinant insulin-like growth
factor I in children with growth hormone insensitivity
syndrome: a clinical research center study. J. Clin.
Endocrinol. Metab. 86, 1504–1510 (2001).
155. Kemp, S. F., Fowlkes, J. L. & Thrailkill, K. M. Efficacy
and safety of mecasermin rinfabate. Expert Opin.
Biol. Ther. 6, 533–538 (2006).
156. Ho, M. W. & O’Brien, J. S. Gaucher’s disease:
deficiency of ‘acid’ -glucosidase and reconstitution of
enzyme activity in vitro. Proc. Natl Acad. Sci. USA 68,
157. Klinge, L. et al. Safety and efficacy of recombinant acid
α-glucosidase (rhGAA) in patients with classical
infantile Pompe disease: results of a phase II clinical
trial. Neuromuscul. Disord. 15, 24–31 (2005).
158. Scott, H. S. et al. Human α-l-iduronidase: cDNA
isolation and expression. Proc. Natl Acad. Sci. USA 88,
159. Bach, G., Friedman, R., Weissmann, B. & Neufeld, E. F.
The defect in the Hurler and Scheie syndromes:
deficiency of α-l-iduronidase. Proc. Natl Acad. Sci. USA
69, 2048–2051 (1972).
160. Kakkis, E. D. et al. Enzyme-replacement therapy in
mucopolysaccharidosis I. N. Engl. J. Med. 344,
161. Muenzer, J. et al. A phase II/III clinical study of enzyme
replacement therapy with idursulfase in
mucopolysaccharidosis II (Hunter syndrome). Genet.
Med. 8, 465–473 (2006).
162. Hopwood, J. J., Bate, G. & Kirkpatrick, P. Galsulfase.
Nature Rev. Drug Discov. 5, 101–102 (2006).
163. Eng., C. M. et al. Safety and efficacy of recombinant
human α-galactosidase A — replacement therapy in
Fabry’s disease. N. Engl. J. Med. 345, 9–16 (2001).
164. Schiffmann, R. et al. Enzyme replacement therapy in
Fabry disease: a randomized controlled trial. JAMA
285, 2743–2749 (2001).
165. Society, A. T. Guidelines for the approach to the patient
with severe hereditary α-1-antitrypsin deficiency.
Am. Rev. Respir. Dis. 140, 1494–1497 (1989).
166. Hershfield, M. S. et al. Treatment of adenosine
deaminase deficiency with polyethylene glycol-modified
adenosine deaminase. N. Engl. J. Med. 316, 589–596
167. Ochs, H. D. & Pinciaro, P. J. Octagam 5%, an
intravenous IgG product, is efficacious and well
tolerated in subjects with primary immunodeficiency
diseases. J. Clin. Immunol. 24, 309–314 (2004).
168. Finfer, S. et al. A comparison of albumin and saline for
fluid resuscitation in the intensive care unit. N. Engl.
J. Med. 350, 2247–2256 (2004).
169. No authors listed. Association between recombinant
human erythropoietin and quality of life and exercise
capacity of patients receiving haemodialysis. Canadian
Erythropoietin Study Group. BMJ 300, 573–578
NATUre reVIeWS | drug discovery
VoLUMe 7 | jANUAry 2008 | 37
© 2008 Nature Publishing Group
170. Laupacis, A. Changes in quality of life and functional
capacity in hemodialysis patients treated with
recombinant human erythropoietin. The Canadian
Erythropoietin Study Group. Semin. Nephrol. 10,
171. Heil, G. et al. A randomized, double-blind,
placebo-controlled, phase III study of filgrastim in
remission induction and consolidation therapy for
adults with de novo acute myeloid leukemia. Blood
90, 4710–4718 (1997).
172. Tarlatzis, B. et al. The use of recombinant human LH
(lutropin alfa) in the late stimulation phase of assisted
reproduction cycles: a double-blind, randomized,
prospective study. Hum. Reprod. 21, 90–94 (2006).
173. Cirelli, R. & Tyring, S. K. Interferons in human
papillomavirus infections. Antiviral Res. 24, 191–204
174. Lindsay, K. L. Therapy of hepatitis C: overview.
Hepatology 26, 71S–77S (1997).
175. Tong, M. J. et al. Treatment of chronic hepatitis C with
consensus interferon: a multicenter, randomized,
controlled trial. Consensus Interferon Study Group.
Hepatology 26, 747–754 (1997).
176. Suzuki, H. & Tango, T. A multicenter, randomized,
controlled clinical trial of interferon alfacon-1 in
comparison with lymphoblastoid interferon-α in
patients with high-titer chronic hepatitis C virus
infection. Hepatol. Res. 22, 1–12 (2002).
177. van Zonneveld, M. et al. Long-term follow-up of
α-interferon treatment of patients with chronic
hepatitis B. Hepatology 39, 804–810 (2004).
178. Giannini, E. et al. Long-term follow up of chronic
hepatitis C patients after α-interferon treatment:
a functional study. J. Gastroenterol. Hepatol. 16,
179. Smalley, R. V. et al. Interferon α combined with
cytotoxic chemotherapy for patients with non-Hodgkin’s
lymphoma. N. Engl. J. Med. 327, 1336–1341 (1992).
180. Quesada, J. R. et al. Treatment of hairy cell leukemia
with recombinant α-interferon. Blood 68, 493–497
181. Allan, N. C., Richards, S. M. & Shepherd, P. C. UK
Medical Research Council randomised, multicentre
trial of interferon-α n1 for chronic myeloid leukaemia:
improved survival irrespective of cytogenetic response.
The UK Medical Research Council’s Working Parties for
Therapeutic Trials in Adult Leukaemia. Lancet 345,
182. No authors listed. Interferon α-2a as compared with
conventional chemotherapy for the treatment of
chronic myeloid leukemia. The Italian Cooperative
Study Group on Chronic Myeloid Leukemia. N. Engl. J.
Med. 330, 820–825 (1994).
183. Misiani, R. et al. Interferon α-2a therapy in
cryoglobulinemia associated with hepatitis C virus.
N. Engl. J. Med. 330, 751–756 (1994).
184. Fried, M. W. et al. Peginterferon α-2a plus ribavirin for
chronic hepatitis C virus infection. N. Engl. J. Med.
347, 975–982 (2002).
185. Zeuzem, S. et al. Peginterferon α-2a in patients with
chronic hepatitis C. N. Engl. J. Med. 343, 1666–1672
186. Heathcote, E. J. et al. Peginterferon α-2a in patients
with chronic hepatitis C and cirrhosis. N. Engl. J. Med.
343, 1673–1680 (2000).
187. Mandelli, F. et al. Maintenance treatment with
recombinant interferon α-2b in patients with multiple
myeloma responding to conventional induction
chemotherapy. N. Engl. J. Med. 322, 1430–1434
188. Perrillo, R. P. et al. A randomized, controlled trial of
interferon α-2b alone and after prednisone withdrawal
for the treatment of chronic hepatitis B. The Hepatitis
Interventional Therapy Group. N. Engl. J. Med. 323,
189. Solal-Celigny, P. et al. Recombinant interferon α-2b
combined with a regimen containing doxorubicin in
patients with advanced follicular lymphoma. Groupe
d’Etude des Lymphomes de l’Adulte. N. Engl. J. Med.
329, 1608–1614 (1993).
190. Manns, M. P. et al. Peginterferon α-2b plus ribavirin
compared with interferon α-2b plus ribavirin for initial
treatment of chronic hepatitis C: a randomised trial.
Lancet 358, 958–965 (2001).
191. Simon, D. M. et al. Treatment of chronic hepatitis C
with interferon α-n3: a multicenter, randomized,
open-label trial. Hepatology 25, 445–448 (1997).
192. Friedmankien, A. Management of condylomata
acuminata with Alferon-N injection, interferon α-n3
(human-leukocyte derived). Am. J. Obstet. Gynecol.
172, 1359–1368 (1995).
193. Panitch, H. et al. Randomized, comparative study of
interferon β-1a treatment regimens in MS: the
EVIDENCE trial. Neurology 59, 1496–1506 (2002).
194. Jacobs, L. D. et al. Intramuscular interferon β-1a
therapy initiated during a first demyelinating event in
multiple sclerosis. CHAMPS Study Group. N. Engl. J.
Med. 343, 898–904 (2000).
195. Byrne, E. Randomized, comparative study of interferon
β-1a treatment regimens in MS: the EVIDENCE trial.
Neurology 60, 1872–1873 (2003).
196. No authors listed. Randomised double-blind placebo-
controlled study of interferon β-1a in relapsing/
remitting multiple sclerosis. PRISMS (Prevention of
Relapses and Disability by Interferon β-1a
Subcutaneously in Multiple Sclerosis) Study Group.
Lancet 352, 1498–1504 (1998).
197. Paty, D. W. & Li, D. K. Interferon β-1b is effective in
relapsing-remitting multiple sclerosis. II. MRI analysis
results of a multicenter, randomized, double-blind,
placebo-controlled trial. UBC MS/MRI Study Group
and the IFNB Multiple Sclerosis Study Group.
Neurology 43, 662–667 (1993).
198. No authors listed. Interferon β-1b in the treatment of
multiple sclerosis: final outcome of the randomized
controlled trial. The IFNB Multiple Sclerosis Study
Group and The University of British Columbia MS/MRI
Analysis Group. Neurology 45, 1277–1285 (1995).
199. Durelli, L. et al. Every-other-day interferon β-1b
versus once-weekly interferon β-1a for multiple
sclerosis: results of a 2-year prospective randomised
multicentre study (INCOMIN). Lancet 359, 1453–
200. Raghu, G. et al. A placebo-controlled trial of interferon
γ-1b in patients with idiopathic pulmonary fibrosis.
N. Engl. J. Med. 350, 125–133 (2004).
201. Key, L. L. Jr et al. Long-term treatment of osteopetrosis
with recombinant human interferon γ. N. Engl. J. Med.
332, 1594–1599 (1995).
202. Ezekowitz, R. A., Dinauer, M. C., Jaffe, H. S.,
Orkin, S. H. & Newburger, P. E. Partial correction of
the phagocyte defect in patients with X-linked chronic
granulomatous disease by subcutaneous interferon
γ. N. Engl. J. Med. 319, 146–151 (1988).
203. Baron, S. et al. The interferons. Mechanisms of action
and clinical applications. JAMA 266, 1375–1383
204. Key, L. L. Jr, Ries, W. L., Rodriguiz, R. M. & Hatcher,
H. C. Recombinant human interferon γ therapy for
osteopetrosis. J. Pediatr. 121, 119–124 (1992).
205. Negrier, S. et al. Recombinant human interleukin-2,
recombinant human interferon α-2a, or both in
metastatic renal-cell carcinoma. Groupe Francais
d’Immunotherapie. N. Engl. J. Med. 338, 1272–1278
206. Atkins, M. B. et al. High-dose recombinant interleukin
2 therapy for patients with metastatic melanoma:
analysis of 270 patients treated between 1985 and
1993. J. Clin. Oncol. 17, 2105–2116 (1999).
207. Rosenberg, S. A. et al. Treatment of patients with
metastatic melanoma with autologous tumor-
infiltrating lymphocytes and interleukin 2. J. Natl
Cancer Inst. 86, 1159–1166 (1994).
208. Atkins, M. B., Kunkel, L., Sznol, M. & Rosenberg, S. A.
High-dose recombinant interleukin-2 therapy in
patients with metastatic melanoma: long-term survival
update. Cancer J. Sci. Am. 6 (Suppl. 1), 11–14 (2000).
209. Goldhaber, S. Z. et al. Randomized controlled trial of
recombinant tissue plasminogen-activator versus
urokinase in the treatment of acute pulmonary-
embolism. Lancet 2, 293–298 (1988).
210. Tow, D. E., Wagner, H. N. & Holmes, R. A. Urokinase
in pulmonary embolism. N. Engl. J. Med. 277,
211. Chesnut, C. H. et al. A randomized trial of nasal spray
salmon calcitonin in postmenopausal women with
established osteoporosis: the prevent recurrence of
osteoporotic fractures study. Am. J. Med. 109,
212. Colman, E., Hedin, R., Swann, J. & Orloff, D. A brief
history of calcitonin. Lancet 359, 885–886 (2002).
213. Body, J. J. et al. A randomized double-blind trial to
compare the efficacy of teriparatide [recombinant
human parathyroid hormone (1–34)] with alendronate
in postmenopausal women with osteoporosis. J. Clin.
Endocrinol. Metab. 87, 4528–4535 (2002).
214. Neer, R. M. et al. Effect of parathyroid hormone
(1–34) on fractures and bone mineral density in
postmenopausal women with osteoporosis. N. Engl.
J. Med. 344, 1434–1441 (2001).
215. Reeve, J. Recombinant human parathyroid hormone.
BMJ 324, 435–436 (2002).
216. Tashjian, A. H. Jr. & Gagel, R. F. Teriparatide [human
PTH(1–34)]: 2.5 years of experience on the use and
safety of the drug for the treatment of osteoporosis.
J. Bone Miner. Res. 21, 354–365 (2006).
217. Heine, R. J. et al. Exenatide versus insulin glargine in
patients with suboptimally controlled type 2 diabetes:
a randomized trial. Ann. Intern. Med. 143, 559–569
218. Tomassetti, P. et al. Treatment of type II gastric
carcinoid tumors with somatostatin analogues.
N. Engl. J. Med. 343, 551–554 (2000).
219. Lamberts, S. W. J., van der Lely, A-. J., de Herder,
W. W. & Hofland, L. J. Drug therapy — Octreotide.
N. Engl. J. Med. 334, 246–254 (1996).
220. Govender, S., Csimma, C., Genant, H. K. & Valentin-
Opran, A. Recombinant human bone morphogenetic
protein-2 for treatment of open tibial fractures.
A prospective, controlled, randomized study of four
hundred and fifty patients. J. Bone Joint Surg. Am. 84,
221. Boden, S. D., Zdeblick, T. A., Sandhu, H. S. & Heim,
S. E. The use of rhBMP-2 in interbody fusion cages.
Definitive evidence of osteoinduction in humans: a
preliminary report. Spine 25, 376–381 (2000).
222. Friedlaender, G. E. et al. Osteogenic protein-1 (bone
morphogenetic protein-7) in the treatment of tibial
nonunions. A prospective, randomized clinical trial
comparing rhOP-1 with fresh bone autograft. J. Bone
Joint Surg. Am. 83, S151–S158 (2001).
223. Feuillan, P. P., Jones, J. V., Barnes, K., Oerter-Klein, K.
& Cutler, G. B. Reproductive axis after discontinuation
of gonadotropin-releasing hormone analog treatment
of girls with precocious puberty: long term follow-up
comparing girls with hypothalamic hamartoma to
those with idiopathic precocious puberty. J. Clin.
Endocrinol. Metab. 84, 44–49 (1999).
224. Jay, N. et al. Ovulation and menstrual function of
adolescent girls with central precocious puberty after
therapy with gonadotropin-releasing-hormone
agonists. J. Clin. Endocrinol. Metab. 75, 890–894
225. Spielberger, R. et al. Palifermin for oral mucositis after
intensive therapy for hematologic cancers. N. Engl. J.
Med. 351, 2590–2598 (2004).
226. Smiell, J. M. et al. Efficacy and safety of becaplermin
(recombinant human platelet-derived growth factor-
BB) in patients with nonhealing, lower extremity
diabetic ulcers: a combined analysis of four randomized
studies. Wound Repair Regen. 7, 335–346 (1999).
227. Embil, J. M. et al. Recombinant human platelet-
derived growth factor-BB (becaplermin) for healing
chronic lower extremity diabetic ulcers: an open-label
clinical evaluation of efficacy. Wound Repair Regen. 8,
228. Wieman, T. J. Clinical efficacy of becaplermin
(rhPDGF-BB) gel. Becaplermin Gel Studies Group.
Am. J. Surg. 176, 74S-79S (1998).
229. Hellgren, L. Cleansing properties of stabilized trypsin
and streptokinase-streptodornase in necrotic leg
ulcers. Eur. J. Clin. Pharmacol. 24, 623–628 (1983).
230. Intravenous nesiritide vs nitroglycerin for treatment of
decompensated congestive heart failure: a randomized
controlled trial. JAMA 287, 1531–1540 (2002).
231. Colucci, W. S. et al. Intravenous nesiritide, a natriuretic
peptide, in the treatment of decompensated congestive
heart failure. Nesiritide Study Group. N. Engl. J. Med.
343, 246–253 (2000).
232. Blasi, J. et al. Botulinum neurotoxin-a selectively
cleaves the synaptic protein snap-25. Nature 365,
233. Jankovic, J. & Brin, M. F. Therapeutic uses of
botulinum toxin. N. Engl. J. Med. 324, 1186–1194
234. Schiavo, G. et al. Tetanus and botulinum-b neurotoxins
block neurotransmitter release by proteolytic cleavage
of synaptobrevin. Nature 359, 832–835 (1992).
235. Patel, B. C. K. et al. A comparison of topical and
retrobulbar anesthesia for cataract surgery.
Ophthalmology 103, 1196–1203 (1996).
236. Aslam, S. et al. Effect of hyaluronidase on ocular
motility and eyelid function in sub-Tenon’s anaesthesia:
randomised controlled trial. Eye 20, 579–582 (2006).
237. Goldman, S. C. et al. A randomized comparison
between rasburicase and allopurinol in children with
lymphoma or leukemia at high risk for tumor lysis.
Blood 97, 2998–3003 (2001).
238. Lincoff, A. M. et al. Bivalirudin and provisional
glycoprotein IIb/IIIa blockade compared with heparin
and planned glycoprotein IIb/IIIa blockade during
percutaneous coronary intervention — REPLACE-2
Randomized Trial. JAMA 289, 853–863 (2003).
38 | jANUAry 2008 | VoLUMe 7
© 2008 Nature Publishing Group
239. Bittl, J. A. et al. Treatment with bivalirudin (hirulog) as
compared with heparin during coronary angioplasty for
unstable or postinfarction angina. N. Engl. J. Med.
333, 764–769 (1995).
240. The GUSTO Investigators. An international randomized
trial comparing four thrombolytic strategies for acute
myocardial infarction. N. Engl. J. Med. 329, 673–682
241. Hunt, D. et al. Isis-3 — a randomized comparison of
streptokinase vs tissue plasminogen-activator vs
anistreplase and of aspirin plus heparin vs aspirin
alone among 41,299 cases of suspected acute
myocardial-infarction. Lancet 339, 753–770 (1992).
242. Anderson, J. L. et al. Multicenter reperfusion trial of
intravenous anisoylated plasminogen streptokinase
activator complex (APSAC) in acute myocardial-
infarction — controlled comparison with intracoronary
streptokinase. J. Am. Coll. Cardiol. 11, 1153–1163
243. Hurwitz, H. et al. Bevacizumab plus irinotecan,
fluorouracil, and leucovorin for metastatic colorectal
cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
244. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W.
Discovery and development of bevacizumab, an anti-
VEGF antibody for treating cancer. Nature Rev. Drug
Discov. 3, 391–400 (2004).
245. Yang, J. C. et al. A randomized trial of bevacizumab,
an anti-vascular endothelial growth factor antibody,
for metastatic renal cancer. N. Engl. J. Med. 349,
246. Kabbinavar, F. et al. Phase II, randomized trial
comparing bevacizumab plus fluorouracil (FU)/
leucovorin (LV) with FU/LV alone in patients with
metastatic colorectal cancer. J. Clin. Oncol. 21, 60–65
247. Wainberg, Z. & Hecht, J. R. A phase III randomized,
open-label, controlled trial of chemotherapy and
bevacizumab with or without panitumumab in the first-
line treatment of patients with metastatic colorectal
cancer. Clin. Colorectal Cancer 5, 363–367 (2006).
248. Keating, M. J. et al. Therapeutic role of alemtuzumab
(Campath-1H) in patients who have failed fludarabine:
results of a large international study. Blood 99,
249. Keating, M. J. et al. Early results of a
chemoimmunotherapy regimen of fludarabine,
cyclophosphamide, and rituximab as initial therapy
for chronic lymphocytic leukemia. J. Clin. Oncol. 23,
250. Di Gaetano, N. et al. Synergism between fludarabine
and rituximab revealed in a follicular lymphoma cell
line resistant to the, cytotoxic activity of either drug
alone. Br. J. Haematology 114, 800–809 (2001).
251. Jazirehi, A. R., Huerta-Yepez, S., Cheng, G. H. &
Bonavida, B. Rituximab (chimeric anti-CD20
monoclonal antibody) inhibits the constitutive nuclear
factor-k B signaling pathway in non-Hodgkin’s
lymphoma B-cell lines: role in sensitization to
chemotherapeutic drug-induced apoptosis. Cancer Res.
65, 264–276 (2005).
252. Genovese, M. C. et al. Abatacept for rheumatoid
arthritis refractory to tumor necrosis factor α
inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).
253. Cohen, S. B. et al. A multicenter double-blind
randomized placebo-controlled trial of Kineret
(anakinra), a recombinant interleukin 1 receptor
antagonist, in patients with rheumatoid arthritis
treated with background methotrexate therapy.
Ann. Rheum. Dis. 63, 1062–1068 (2004).
254. Fleischmann, R. M. et al. Anakinra, a recombinant
human interleukin-1 receptor antagonist
(r-metHuIL-1ra), in patients with rheumatoid arthritis:
a large, international, multicenter, placebo-controlled
trial. Arthritis Rheum. 48, 927–934 (2003).
255. Tesser, J. et al. Concomitant medication use in a large,
international, multicenter, placebo controlled trial of
anakinra, a recombinant interleukin 1 receptor
antagonist, in patients with rheumatoid arthritis.
J. Rheumatol. 31, 649–654 (2004).
256. Olsen, N. J. & Stein, C. M. Drug therapy — new drugs
for rheumatoid arthritis. N. Engl. J. Med. 350,
257. Weinblatt, M. E. et al. Adalimumab, a fully human
anti-tumor necrosis factor a monoclonal antibody, for
the treatment of rheumatoid arthritis in patients taking
concomitant methotrexate — The ARMADA trial.
Arthritis Rheum. 48, 35–45 (2003).
258. Ellis, C. N. & Krueger, G. G. Treatment of chronic
plaque psoriasis by selective targeting of memory
effector T lymphocytes. N. Engl. J. Med. 345,
259. Krueger, G. G. et al. A randomized, double-blind,
placebo-controlled phase III study evaluating efficacy
and tolerability of 2 courses of alefacept in patients
with chronic plaque psoriasis. J. Am. Acad. Dermatol.
47, 821–833 (2002).
260. Lebwohl, M. et al. A novel targeted T-cell modulator,
efalizumab, for plaque psoriasis. N. Engl. J. Med. 349,
261. Gordon, K. B. et al. Efalizumab for patients with
moderate to severe plaque psoriasis: a randomized
controlled trial. JAMA 290, 3073–3080 (2003).
262. Miller, D. H. et al. A controlled trial of natalizumab for
relapsing multiple sclerosis. N. Engl. J. Med. 348,
263. Hillmen, P. et al. Effect of eculizumab on hemolysis and
transfusion requirements in patients with paroxysmal
nocturnal hemoglobinuria. N. Engl. J. Med. 350,
264. Hillmen, P. et al. The complement inhibitor
eculizumab in paroxysmal nocturnal hemoglobinuria.
N. Engl. J. Med. 355, 1233–1243 (2006).
265. Denton, M. D., Magee, C. C. & Sayegh, M. H.
Immunosuppressive strategies in transplantation.
Lancet 353, 1083–1091 (1999).
266. Frickhofen, N. et al. Treatment of aplastic-anemia with
antilymphocyte globulin and methylprednisolone
with or without cyclosporine. N. Engl. J. Med. 324,
267. Soulillou, J. P. et al. Randomized controlled trial of a
monoclonal-antibody against the interleukin-2 receptor
(33b3.1) as compared with rabbit antithymocyte
globulin for prophylaxis against rejection of renal-
allografts. N. Engl. J. Med. 322, 1175–1182 (1990).
268. Nashan, B. et al. Randomised trial of basiliximab
versus placebo for control of acute cellular rejection in
renal allograft recipients. CHIB 201 International Study
Group. Lancet 350, 1193–1198 (1997).
269. Vincenti, F. et al. Interleukin-2-receptor blockade with
daclizumab to prevent acute rejection in renal
transplantation. Daclizumab Triple Therapy Study
Group. N. Engl. J. Med. 338, 161–165 (1998).
270. No authors listed. A comparison of tacrolimus (FK 506)
and cyclosporine for immunosuppression in liver
transplantation. The U.S. Multicenter FK506 Liver
Study Group. N. Engl. J. Med. 331, 1110–1115 (1994).
271. Cosimi, A. B. et al. Treatment of acute renal allograft
rejection with OKT3 monoclonal antibody.
Transplantation 32, 535–539 (1981).
272. Cosimi, A. B. et al. A randomized clinical trial
comparing OKT3 and steroids for treatment of hepatic
allograft rejection. Transplantation 43, 91–95 (1987).
273. Busse, W. et al. Omalizumab, anti-IgE recombinant
humanized monoclonal antibody, for the treatment of
severe allergic asthma. J. Allergy Clin. Immunol. 108,
274. Casale, T. B. et al. Effect of omalizumab on symptoms
of seasonal allergic rhinitis: a randomized controlled
trial. JAMA 286, 2956–2967 (2001).
275. Milgrom, H. et al. Treatment of childhood asthma with
anti-immunoglobulin E antibody (omalizumab).
Pediatrics 108, e36 (2001).
276. No authors listed. Randomised placebo-controlled trial
of abciximab before and during coronary intervention
in refractory unstable angina: the CAPTURE Study.
Lancet 349, 1429–1435 (1997).
277. Antman, E. M. et al. Abciximab facilitates the rate and
extent of thrombolysis: results of the thrombolysis in
myocardial infarction (TIMI) 14 trial. The TIMI 14
Investigators. Circulation 99, 2720–2732 (1999).
278. Ibbotson, T., McGavin, J. K. & Goa, K. L. Abciximab:
an updated review of its therapeutic use in patients
with ischaemic heart disease undergoing percutaneous
coronary revascularisation. Drugs 63, 1121–1163
279. Trainer, P. J. et al. Treatment of acromegaly with the
growth hormone-receptor antagonist pegvisomant.
N. Engl. J. Med. 342, 1171–1177 (2000).
280. van der Lely, A. J. et al. Long-term treatment of
acromegaly with pegvisomant, a growth hormone
receptor antagonist. Lancet 358, 1754–1759 (2001).
281. Ruha, A. M. et al. Initial postmarketing experience
with Crotalidae polyvalent immune Fab for treatment
of rattlesnake envenomation. Ann. Emerg. Med. 39,
282. Dart, R. C. & McNally, J. Efficacy, safety, and use of
snake antivenoms in the United States. Ann. Emerg.
Med. 37, 181–188 (2001).
283. Smith, T. W., Haber, E., Yeatman, L. & Butler, V. P. Jr.
Reversal of advanced digoxin intoxication with Fab
fragments of digoxin-specific antibodies. N. Engl. J.
Med. 294, 797–800 (1976).
284. Antman, E. M., Wenger, T. L., Butler, V. P. Jr, Haber, E.
& Smith, T. W. Treatment of 150 cases of life-
threatening digitalis intoxication with digoxin-specific
Fab antibody fragments. Final report of a multicenter
study. Circulation 81, 1744–1752 (1990).
285. Brown, D. M. et al. Ranibizumab versus verteporfin
for neovascular age-related macular degeneration.
N. Engl. J. Med. 355, 1432–1444 (2006).
286. Kaminski, M. S. et al. Radioimmunotherapy with iodine
(131)I tositumomab for relapsed or refractory B-cell
non-Hodgkin lymphoma: updated results and long-
term follow-up of the University of Michigan
experience. Blood 96, 1259–1266 (2000).
287. Press, O. W. et al. A phase 2 trial of CHOP
chemotherapy followed by tositumomab/iodine I 131
tositumomab for previously untreated follicular non-
Hodgkin lymphoma: Southwest Oncology Group
Protocol S9911. Blood 102, 1606–1612 (2003).
288. Aman, J. & Wranne, L. Hypoglycaemia in childhood
diabetes. II. Effect of subcutaneous or intramuscular
injection of different doses of glucagon. Acta Paediatr.
Scand. 77, 548–553 (1988).
289. Carson, M. J. & Koch, R. Clinical studies with glucagon
in children. J. Pediatr. 47, 161–170 (1955).
290. Jowell, P. S. et al. A double-blind, randomized, dose
response study testing the pharmacological efficacy of
synthetic porcine secretin. Aliment. Pharmacol. Ther.
14, 1679–1684 (2000).
291. Somogyi, L., Ross, S. O., Cintron, M. & Toskes, P. P.
Comparison of biologic porcine secretin, synthetic
porcine secretin, and synthetic human secretin in
pancreatic function testing. Pancreas 27, 230–234
292. Oberg, K. Neuroendocrine gastrointestinal tumours.
Ann. Oncol. 7, 453–463 (1996).
293. Maguire, R. T., Pascucci, V. L., Maroli, A. N. & Gulfo,
J. V. Immunoscintigraphy in patients with colorectal,
ovarian, and prostate-cancer — results with site-specific
immunoconjugates. Cancer 72, 3453–3462 (1993).
294. Hughes, K. et al. Use of carcinoembryonic antigen
radioimmunodetection and computed tomography for
predicting the resectability of recurrent colorectal
cancer. Ann. Surg. 226, 621–631 (1997).
295. Goldenberg, D. M. et al. Carcinoembryonic antigen
immunoscintigraphy complements mammography
in the diagnosis of breast carcinoma. Cancer 89,
296. Balaban, E. P. et al. Detection and staging of small-cell
lung-carcinoma with a technetium-labeled monoclonal-
antibody: a comparison with standard staging
methods. Clin. Nucl. Med. 17, 439–445 (1992).
297. Johnson, L. L. et al. Antimyosin imaging in acute
transmural myocardial infarctions — results of a
multicenter clinical trial. J. Am. Coll. Cardiol. 13,
298. Kipper, S. L. et al. Neutrophil-specific Tc-99m-labeled
anti-CD15 monoclonal antibody imaging for diagnosis
of equivocal appendicitis. J. Nucl. Med. 41, 449–455
299. Chapman, W. C., et al. A phase 3, randomized, double-
blind comparative study of the efficacy and safety of
topical recombinant human thrombin and bovine
thrombin in surgical hemostasis. J. Am. Coll. Surg.
205, 256–265 (2007).
300. Food and Drug Administration (FDA). Product Approval
Information: Thrombin, Topical (Human), Updated
October 23, 2007. FDA web site [online], <http://
We thank A. H. Tashjian Jr for many helpful discussions and
expert review of the manuscript. D.E.G. is supported by NIH
grants R37HL032854 and U54HL070819. Q.J.B. is supp-
orted by NIH grant T32GM07753. Portions of this article
have been published in abbreviated form (Golan, D. E. et al.
Principles of Pharmacology: The Pathophysiologic Basis of
Drug Therapy (Lippincott Williams & Wilkins, 2004); Golan,
D.E. et al. Principles of Pharmacology: The Pathophysiologic
Basis of Drug Therapy, 2nd edn (Lippincott Williams &
Wilkins, 2007)), and are adapted with permission.
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