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ANTIBODY-DRUG CONJUGATES AND T-DM1
What Can We Learn about Antibody-Drug Conjugates from the
T-DM1 Experience?
Francisco J. Esteva, MD, PhD, Kathy D. Miller, MD, and Beverly A. Teicher, PhD
OVERVIEW
Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or
antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed
toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates
has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not
sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation.
Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or
antibody fragment–protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates,
and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the
conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule
components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibodyradionuclide
conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40
antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving
treatment for patients with cancer.
The challenges posed by the development of therapeutic
antibody-drug conjugates (ADCs) are formidable. Over
the past 30 years, many cell surface proteins that have selective
aberrant expression on malignant cells or are aberrantly
highly expressed on the surface of malignant cells have been
identifıed. In many cases, specifıc antibodies that bind tightly
to malignant cell surface proteins were developed. However,
these antibodies often were not active antitumor agents.
ADCs provide an opportunity to make use of antibodies that
are specifıc to cell surface proteins. 1 Successful ADCs have
improved tumor specifıcity and potency compared with traditional
drugs. 2,3 Heterogeneity of antibody target expression
on the tumor surface, and expression of the antigen by normal
tissues, can limit the effectiveness of ADCs. For some
hematologic malignancies, antigen expression is specifıc and
homogeneous.
Early ADCs were composed of tumor-specifıc murine
monoclonal antibodies covalently linked to anticancer drugs,
such as doxorubicin, vinblastine, and methotrexate. These
early conjugates were evaluated in human clinical trials but
had limited success because of immunogenicity, lack of potency,
and insuffıcient selectivity for tumor versus normal
tissue. The lessons learned from these early explorations led
to improvements in all aspects of antibody conjugate therapeutics
and, hence, to renewed interest in ADC technology. 4
Immunogenicity was overcome by replacing murine antibodies
with humanized or fully human antibodies. Potency
was improved by using drugs that were 100- to 1,000-fold
more potent than previously used drugs. Selectivity was addressed
by performing more careful target and antibody selection.
As a result of such improvements, gemtuzumab
ozogamicin (Mylotarg; Pfızer, New York, NY) was granted
accelerated U.S. Food and Drug Administration (FDA) approval
for the treatment of acute myelogenous leukemia in
2000, becoming the fırst commercially available ADC. However,
gemtuzumab ozogamicin was withdrawn from the market
in 2010 because, in postmarketing follow-up clinical
trials, it failed to meet the prospective effıcacy targets. Two
ADCs, trastuzumab emtansine (T-DM1, Kadcyla; Genentech/Roche,
South San Francisco, CA) and brentuximab vedotin
(SGN-35; Adcetris, Seattle Genetics, Seattle, WA;
Millennium/Takeda, Boston, MA), reached FDA approval in
2014 and 2011, respectively, for treatment of metastatic
breast cancer and refractory Hodgkin lymphoma and systemic
anaplastic large cell lymphoma, respectively. More
than 40 ADCs are in clinical trials (Table 1).
From the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; National Cancer
Institute at the National Institutes of Health, Bethesda, MD.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Beverly A. Teicher, PhD, Molecular Pharmacology Branch, National Cancer Institute, 9609 Medical Center Dr., Room 4-W602, MSC 9735, Bethesda, MD 20892;
email: beverly.teicher@nih.gov.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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