Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy
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molecules Review Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy Hao Chen †, Zongtao Lin † ID , Kinsie E. Arnst, Duane D. Miller ID and Wei Li * Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN 38163, USA; [email protected] (H.C.); [email protected] (Z.L.); [email protected] (K.E.A.); [email protected] (D.D.M.) * Correspondence: [email protected]; Tel.: +1-901-448-7532; Fax: +1-901-448-6828 † These authors contributed equally to this work. Received: 12 July 2017; Accepted: 29 July 2017; Published: 1 August 2017 Abstract: Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy. Since tubulin inhibitors are one of the most successful cytotoxic drugs in the ADC armamentarium, this review focuses on the progress in tubulin inhibitor-based ADCs, as well as lessons learned from the unsuccessful ADCs containing tubulin inhibitors. This review should be helpful to facilitate future development of new generations of tubulin inhibitor-based ADCs for cancer therapy. Keywords: antibody-drug conjugates; cytotoxic payloads; linker; monoclonal antibody; site-specific conjugation; tubulin inhibitors 1. Introduction Cancer is one of the leading causes of death in the United States, accounting for about half a million deaths every year [1]. In the early days of cancer treatment, conventional chemotherapy dominated the field with an improvement in cancer-related mortality. Early chemotherapeutic agents included, but were not limited to, DNA-damaging agents (such as nitrogen mustard, anthracyclines, and cyclophosphamide), tubulin inhibitors (such as the vinca alkaloids vinblastine and vincristine, and taxane diterpenes like taxol), and antifolate agents (such as methotrexate, pemetrexed, proguanil, pyrimethamine, and trimethoprim). A significant proportion of cancer patients suffer from acquired resistance or relapse after long-term chemotherapy treatment. Moreover, these drugs usually have nonspecific toxicity which kills not only tumor cells, but also damages normal tissues and causes serious side effects that often limit their efficacy [2]. In contrast to chemotherapy, targeted therapy is considered a more efficacious and safer cancer treatment and has gained increasing interest in recent years. Targeted therapy blocks the rapidly dividing cancer cells by interfering with the specific targeted molecules needed for tumor growth [3]. The main categories of current targeted cancer therapy are small molecules (e.g., serine/threonine kinase inhibitors and tyrosine-kinase inhibitors), monoclonal antibodies (mAbs), and antibody-drug conjugates (ADCs). One of the most successful small-molecule targeted therapeutic agents is imatinib mesylate, a kinase inhibitor used for chronic myelogenous leukemia and gastrointestinal stromal Molecules 2017, 22, 1281; doi:10.3390/molecules22081281 www.mdpi.com/journal/molecules Molecules 2017, 22, 1281 2 of 28 tumor [4]. Other examples include erlotinib and bortezomib for treating non-small cell lung cancer Molecules 2017, 22, 1281 2 of 27 (NSCLC) and multiple myeloma, respectively [5,6]. Another emerging targeted therapy is monoclonal antibody(NSCLC) (mAb) and therapy,multiplealso myeloma, known respectively as immunotherapy [5,6]. Another [7]. The emerging mAbs aretargeted capable therapy of binding is specificmonoclonal tumor-associated antibody (mAb) antigens therapy, and also inducing known cancer as immunotherapy cell death through [7]. The antibody-dependent mAbs are capable of cell cytotoxicity,binding specific complement-dependent tumor-associated cytotoxicity,antigens and or inducing interference cancer with cell signaling death through pathways; antibody- thus they offerdependent a tumor-targeted cell cytotoxicity, treatment complement-dependent approach [8,9]. Targeted cytotoxicity, mAb therapy or interference is used to treatwith manysignaling cancers includingpathways; non-Hodgkin’s thus they offer lymphoma, a tumor-targeted colorectal treatmen cancer,t approach head/neck [8,9]. cancer, Target anded mAb breast therapy cancer. is However, used small-moleculeto treat many or cancers mAb targetedincluding therapy non-Hodgkin’s alone often lymphoma, shows colorectal inadequate cancer, therapeutic head/neck activity cancer, due and to its lowbreast cytotoxicity cancer. and However, weak penetrationsmall-molecule into or solid mAb tumors. targeted An therapy improved alone approach often shows to overcome inadequate these therapeutic activity due to its low cytotoxicity and weak penetration into solid tumors. An improved limitations is to create ADCs. approach to overcome these limitations is to create ADCs. ADC is a complex molecule composed of a mAb conjugated with a highly potent cytotoxic drug ADC is a complex molecule composed of a mAb conjugated with a highly potent cytotoxic drug (or payload)(or payload) through through an appropriate an appropriate linker linker (Figure (Figure1)[ 10 1), 11[10,11].]. An ADCAn ADC is designed is designed as targeted as targeted therapy, whichtherapy, targets which and kills targets only and cancer kills cellsonly whilecancer sparing cells while healthy sparing cells. healthy The development cells. The development of ADCs faced of a numberADCs of faced challenges a number in theof challenges early 1970s. in the The early first 197 set0s. of The ADCs, first preparedset of ADCs, by prepared conjugating by conjugating murine KS1/4 antibodymurine with KS1/4 the antibody cytotoxic with drug the methotrexatecytotoxic drug ormeth theotrexate BR96 antibodyor the BR96 conjugated antibody conjugated with doxorubicin, with weredoxorubicin, less active than were their less active parent than drugs their [12 parent–14]. drug The failures [12–14]. of The early failure ADCs of resultedearly ADCs from resulted several from factors: (a) theseveral chimeric factors: or murine(a) the antibodieschimeric or used murine in ADCs antibodies could elicitused immunogenicin ADCs could responses elicit immunogenic and cause fast clearanceresponses in circulation; and cause fast (b) theclearance cytotoxic in circulation; drug was (b) insufficiently the cytotoxic potent, drug was and insufficiently further conjugation potent, and might leadfurther to decreased conjugation potency; might (c) lead inappropriate to decreased linkage potency; and (c) theinappropriate poor selection linkage of antigenand the poor could selection lead to the failureof antigen of an ADC. could lead to the failure of an ADC. FigureFigure 1. The1. The general general components components of ofADC. ADC. SelectionSelection pr principlesinciples of of antibody, antibody, comparison comparison between between non-specificnon-specific and and specific specific conjugations, conjugations, and descriptionsand descriptions on how on thehow drug the isdrug released is released and its mechanismand its of action.mechanism of action. Later ADCs achieved success after a better understanding of the basic requirements for their Later ADCs achieved success after a better understanding of the basic requirements for their design. First, the application of humanized and human antibodies has greatly reduced the problems design.caused First, by theimmunogenicity. application of Second humanized, internalizing and human antigens antibodies as tumo hasr targets greatly allowed reduced the thedesign problems of causedmore by functional immunogenicity. antitumor Second, antibodies. internalizing Third, un antigensderstanding as tumor the targetsmechanisms allowed of theaction design (protein of more functionaluptake) antitumor of ADCs in antibodies. mammalian Third, cells helped understanding design different the mechanisms types of linkers, of action which (protein facilitated uptake) the of ADCsrelease in mammalian of payload cellsinside helped the tumors. design Finally, different thetypes discovery of linkers, of new which cytotoxic facilitated compounds the release with of payloadpicomolar inside IC the50 tumors.values further Finally, propelled the discovery the success of new of cytotoxic ADCs [15]. compounds ADCs are with now picomolar powerful IC 50 valuestherapeutics further propelled enabling the wider success therapeutic of ADCs window [15]. ADCss, improved are now pharmacokinetic/pharmacodynamic powerful therapeutics enabling wider therapeutic(PK/PD) windows, profiles, and improved enhanced pharmacokinetic/pharmacodynamic efficacies. The first ADC, gemtuzumab (PK/PD) ozogamicin profiles, (Mylotarg and enhanced®, Molecules 2017, 22, 1281 3 of 28 efficacies.Molecules The 2017, first 22, 1281 ADC, gemtuzumab ozogamicin (Mylotarg®, Pfizer/Wyeth-Ayerst Laboratories,3 of 27 New York, NY, USA), was approved by the US Food and Drug Administration (FDA) in 2000 (later Pfizer/Wyeth-Ayerst Laboratories, New York, NY, USA), was approved by the US Food and Drug withdrawn from the market in 2010 due to toxicity concerns and no sufficient clinical benefit)