Editorial pubs.acs.org/molecularpharmaceutics
Antibody−Drug Conjugates (ADCs): Magic Bullets at Last!
E
tissue is localized in a solid tumor 24 h after intravenous administration of antibody.5 Furthermore, conjugates of several conventional chemotherapeutic drugs already in clinical use in the 1980s failed to show clinical benefit in clinical trials, likely due to insufficient delivery of such moderately cytotoxic agents.6 Thus, the potency of the conjugated cytotoxic agent should be sufficiently high so that it can kill tumor cells at the amounts delivered by antibody retention in the tumor. This insight ultimately led to the development of two classes of highly potent tubulin-acting agents as payloads for ADCs that have yielded two ADCs approved for clinical use. The first of these ADCs, brentuximab vedotin (ADCETRIS), made by conjugation of an auristatin to an anti-CD30 antibody, received accelerated approval from FDA in August 2011 for treating patients with relapsed Hodgkin lymphoma and patients with relapsed or refractory anaplastic large cell lymphoma. Then, in February 2013, ado-trastuzumab emtansine (KADCYLA), a conjugate of a maytansinoid with the anti-HER2 antibody trastuzumab, received full approval from FDA for treating patients with HER2-positive metastatic breast cancer that had progressed on or after a trastuzumab (HERCEPTIN)containing regimen, the first ADC to receive approval based on a randomized phase III study. Brentuximab vedotin and adotrastuzumab emtansine fulfill the long-awaited promise of the ADC field to make highly active, well-tolerated anticancer agents. Their success has reinvigorated the research efforts by the pharmaceutical and biotechnology industries to develop ADC molecules to improve cancer therapies, as evident by the fact that the number of such molecules in clinical trials at time of writing numbers close to 50. The first three articles of this special issue of Molecular Pharmaceutics devoted to ADCs describe the preclinical evaluation of ADCs made with potent tubulin-binding agents. The article by Hong et al. describes studies that led to the design of coltuximab ravtansine, a maytansinoid-containing ADC targeting the B cell antigen, CD19, expressed on malignant B cells. This ADC has achieved proof of concept in phase II clinical trials in diffuse large B cell lymphoma patients. Leong and co-workers describe validation of B7H4 as a target for an ADC by virtue of overexpression on subtypes of breast cancer with only limited normal tissue expression. The authors present preclinical results for an anti-B7H4 ADC that uses the clinically validated linker-drug moiety vedotin (monomethyl auristatin E with a valine-citrulline-PAB linker) conjugated to an engineered cysteine residue that replaces alanine at position 114 (Kabat numbering) of the heavy chain constant region of the antibody. The ADC produces durable responses in tumor xenograft models as well as in patientderived xenograft models. A paper by Hu and colleagues focuses on the use of a mouse model engineered to express human trophoblast glycoprotein for preclinical assessment of the pharmacokinetics and pharmacodynamics of an ADC
ver since oncologists such as Sidney Farber and Emil “Tom” Frei introduced cytotoxic chemotherapy as a treatment modality for treating cancer, research scientists have sought to increase the specificity of such treatments by developing compounds having greater selectivity for killing cancer cells. In fact, the notion of combining, in a single molecule, specific binding to a diseased cell or organism with a toxic activity for that cell or organism was first articulated by the remarkable German scientist, Paul Ehrlich, more than 100 years ago.1 Ehrlich coined the term “magic bullets” to describe such molecules. As the specific binding properties and protein structure of antibodies became known, there were early attempts to conjugate cytotoxic drugs to serum immunoglobulins to provide specificity to such agents.2 However, it was not until the invention of monoclonal antibodies in 19753 that the concept that antibodies could provide to a cell-killing agent the selective binding envisaged by Ehrlich became the subject of a large research effort. From the point of view of the medicinal chemist developing anticancer agents, attaching cytotoxic effector molecules to antibodies to create antibody−drug conjugates (ADCs) provides a mechanism for improving the therapeutic window of the cytotoxic agent via selective delivery and uptake of the cytotoxin to the cancer cells by virtue of the specific binding of the antibody moiety to cell surfaces. At the same time, conjugation of the cytotoxic agent to the large hydrophilic protein restricts penetration of the cytotoxin across cellular membranes of normal cells to which the antibody does not bind. One may think of an ADC as a prodrug that is activated within tumor cells to release the active drug. Furthermore, the cytotoxic agent acquires the in vivo distribution properties of the immunoglobulin with a potentially favorable effect on reducing systemic toxicity. Antibody technology advanced rapidly in the 1980s and 1990s, and four of the most commercially successful anticancer drugs are monoclonal antibodies, rituximab, trastuzumab, cetuximab, and bevacizumab.4 However, considering the size of the effort in the past three decades to apply antibody technology to a large number of target antigens, the yield of successful anticancer agents has been modest. By the time cancer is diagnosed, the malignant cells have evolved to evade immunological mechanisms for cell elimination such as those triggered upon binding of antibodies to cell surface molecules. Thus, the view developed that the activity of antibodies needed to be enhanced in order to fully exploit their exquisite specificity. One approach to enhancing the cell-killing functions of antibodies is to arm them by conjugation of cytotoxic effector molecules. The development of ADCs for treating cancer thus combines the skills of the antibody engineer with those of the medicinal chemist in attempting to turn antibodies into potent, yet well-tolerated, anticancer agents. As the field of anticancer antibodies and ADCs developed, there were several key learnings that guided subsequent research. With respect to biodistribution of antibodies, it was found that only about 0.01% of the injected dose per gram of © 2015 American Chemical Society
Special Issue: Antibody-Drug Conjugates Published: June 1, 2015 1701
DOI: 10.1021/acs.molpharmaceut.5b00302 Mol. Pharmaceutics 2015, 12, 1701−1702
Molecular Pharmaceutics
Editorial
those antigens that do not internalize, targets that are generally thought of as not being useful as ADC targets. In conclusion, this volume of Molecular Pharmaceutics provides a sampling of what is now a burgeoning field, focused on delivering further on the promise of highly active, yet welltolerated, compounds that will improve the treatment options for patients with cancer.
directed toward this cell-surface glycoprotein that is now in clinical development. There are six articles concerning analysis of ADCs. Goldmacher and colleagues present an analysis of the drugload distribution of maytansinoid ADCs where conjugation utilizes the amino groups of lysine residues of the antibodies. Their analysis indicates that a binomial distribution most closely models the experimental findings. Fishkin presents a microscale method for determination of drug extinction coefficients, especially useful when only small quantities of a novel payload are available in the early stages of research, while Salomon and Singh describe a sensitive ELISA method for measuring catabolites of the payload moiety, useful for studying the rate of generation of such catabolites in cancer cells. Widdison and colleagues describe the synthesis of metabolites of maytansinoid-ADCs, and confirm that human liver microsomes can generate oxidation products from the thiolcontaining maytansinoids released intracellularly by some ADCs. These oxidation products have reduced cytotoxicity relative to maytansine. A review article by Valliere-Douglass et al. details approaches to characterizing ADCs made using the interchain disulfide bonds as sites of attachment of payload. Their review nicely illustrates the great utility of mass spectrometry in the assessment of the quality of an ADC. The work of Cockrell and co-workers provides evidence that the light-sensitivity of an ADC should be evaluated during development, as product quality may be affected by photoinduced aggregation. A focus of much research in the ADC field is to explore the potential of new payloads beyond the two utilized within the clinically approved ADC products, and a few examples are included in this special issue. Maderna and Leverett review elegant work to develop new auristatins with the goal of improving upon the therapeutic window of the clinically validated vcMMAE linker-payload format. There is also great interest in the ADC field in cytotoxic effector molecules that target DNA. The paper by Elgersma and co-workers describes the structure and preclinical evaluation of an ADC which targets HER2, and which uses a duocarmycin payload. This ADC has recently advanced into phase I clinical evaluation. Govindan et al. describe the design and preclinical evaluation of another ADC in phase I clinical evaluation, one which targets the topoisomerase inhibitor, SN-38, to CEACAM5-expressing tumor cells. This payload is thought of as being only moderately toxic, and challenges the dogma that an ADC payload needs to be highly cytotoxic to achieve clinical success. Another focus of research for potential improvement in ADC design, with the goal of further improvement in therapeutic index, is in evaluation of various approaches to site-specific linkage of the payloads to particular sites on the antibody. Three such approaches are described in this issue. Hallam and colleagues review coupling strategies utilizing the incorporation of unnatural amino acids which can provide for unique and specific conjugation chemistries, while the article by Lhospice et al. describes an approach to modifying antibodies at specific sites by exploiting the bacterial enzyme, transglutaminase, for site-specific modification at selected glutamine residues. Godwin and co-workers describe a chemical approach to the generation of relatively homogeneous ADCs by using a reagent which bridges across the eight cysteine residues that normally form the four disulfide bonds of an IgG1 molecule. The final article in this special volume is a review by Casi and Neri of the approaches for extending ADC technologies to
John M. Lambert,* Guest Editor
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ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Ehrlich, P. In Collected Papers of Paul Ehrlich; Himmelweit, F., Ed.; Pergamon Press: London, 1956; Vol. 2, pp 442−447. (2) DeCarvalho, S.; et al. Coupling of cyclic chemotherapeutic compounds to immune gamma-globulin. Nature 1964, 202, 255−258. (3) Kohler, G.; Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975, 256, 495− 497. (4) Scott, A. M. Monoclonal antibodies in cancer therapy. Cancer Immun. 2012, 12, 14−22. (5) Sedlacek, H.-H.; et al. Antibodies as Carriers of Cytotoxicity; Contributions to Oncology, Vol. 43; Huber, H., Queisser, W., Eds.; Karger: Basel, 1992; pp 1−145. (6) Chari, R. V. J. Targeted delivery of chemotherapeutics: tumoractivated prodrug therapy. Adv. Drug Delivery Rev. 1998, 31, 89−105.
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DOI: 10.1021/acs.molpharmaceut.5b00302 Mol. Pharmaceutics 2015, 12, 1701−1702
