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Antibody-Drug Conjugates (Adcs) – Biotherapeutic Bullets

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Antibody-Drug Conjugates (Adcs) – Biotherapeutic Bullets Sean L Kitson Antibody-Drug Conjugates (ADCs) – Biotherapeutic bullets SEAN L KITSON*, DEREK J QUINN, THOMAS S MOODY, DAVID SPEED, WILLIAM WATTERS, DAVID ROZZELL *Corresponding author Almac, Department of Biocatalysis and Isotope Chemistry, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, United Kingdom (chimeric human-murine IgG1 targeting EGF receptor) and KEYWORDS panitumumab (human IgG2 targeting EGF receptor) for the Antibody-drug conjugate; ADC; monoclonal antibody; treatment of metastatic colorectal cancer (5). cancer; carbon-14; linker; immunotherapy. This technology of tailoring MAbs has been exploited to develop delivery systems for radionuclides to image and treat a variety of cancers (6). This led to the hypothesis that a ABSTRACT cancer patient would first receive a radionuclide antibody capable of imaging the tumour volume. The images of the Immunotherapies especially targeted towards oncology, tumour are obtained by using one or more combinations of based on antibody-drug conjugates (ADCs) have the following methods: planar imaging; single photon recently been boosted by the US Food and Drug emission computed tomography (SPECT) and positron Administration approval of Adcetris to treat Hodgkin’s emission tomography (PET) (7). These techniques can be lymphoma and Kadcyla for metastatic breast cancer. extended to hybrid imaging systems incorporating PET (or The emphasis of this article is to provide an overview of SPECT) with computed tomography (CT) or magnetic the design of ADCs in order to examine their ability to 30 resonance imaging (MRI) (8). find and kill tumour cells. A particular focus will be on the relationship between the cytotoxic drug, chemical The imaging process is first used to locate the precise position linker and the type of monoclonal antibody (MAb) used of the tumour and ascertain the appropriate level of the to make up the components of the ADC. Furthermore, antibody retained by the body. Then the same antibody can the article will conclude on a carbon-14 labelled linker be labelled with a radionuclide to deliver a therapeutic strategy for ADCs to be utilised in absorption, distribution, radiation dose in order to kill the cancerous cells. This metabolism and excretion (ADME) studies towards approach has led to radionuclide-antibody conjugates (RACs) regulatory new drug approval requirements. being successfully developed to target CD20 antigens for the treatment of non-Hodgkin’s lymphoma (NHL). These include ibritumomab tiuxetan (Zevalin) conjugated to indium-111 for INTRODUCTION imaging and yttrium-90 for therapy approved in 2002 and iodine-131 tositumomab (Bexxar) approved in 2003 (9). n 2012, the US Food and Drug Administration (FDA) gave Furthermore, the ‘biotherapeutic bullet’ approach of ADCs, approval to 39 drugs and this was the highest number since transporting a cytotoxic drug to the tumour site, to limit the Ithe mid 1990s (1). According to market analysis, the outlook damage to the surrounding healthy cells is an attractive remains strong for at least 35 new drug approvals per year until prospect for investors. The market for antibody-based 2016 (2). The next blockbuster drug discoveries may well therapeutics continues to expand - especially in the area of emerge from a class of targeted cell based oncology - contributing to global revenues of US$50 billion immunotherapeutics called antibody-drug conjugates (ADCs). (10). This is due to successful biopharmaceutical partnerships These are being developed by biopharmaceutical companies (11) for developing the ADC platform and is demonstrated by as the next generation of cancer treatments (3). numerous clinical trials (12). The first antibody targeted therapy came in 1986 with the FDA The first FDA approved antibody-drug conjugate was approval of OKT3 to treat organ rejection. This involved the use Mylotarg (gemtuzumab ozogamicin) in 2000, for the of a murine IgG2a monoclonal antibody (MAb) to target the treatment of acute myeloid leukaemia (AML) (13). This ADC CD3 antigen, which is a membrane protein on the surface of targeted the CD33 antigen and a decade later was T-cells (4). Further technologies produced a number of G-type voluntarily withdrawn from the US market due to a narrow immunoglobulins (IgG) to target oncological conditions: therapeutic window and lack of target-dependence (14). rituximab (chimeric human-murine IgG1 targeting CD20 Consequently, this valuable knowledge gained from early antigen, non-Hodgkin’s lymphoma), trastuzumab (humanized ADC development has improved understanding of how to IgG1 targeting HER2 antigen, breast cancer) and connect antibodies to drugs (15). This technology is producing alemtuzumab (humanized IgG1 targeting CD52 antigen, linkers with an acceptable biological half-life, so that the chronic lymphocytic leukaemia). Others include desired target cell can be reached with limited side effects to bevacizumab (humanized IgG1 targeting VEGF), cetuximab the patient (16). Monographic supplement series CROs/CMOs - Chimica Oggi - Chemistry Today - vol. 31(4) July/August 2013 cros/cmos In 2011, the next breakthrough in ADCs came with the MECHANISM OF ACTION OF ADCS accelerated FDA approval of Adcetris (brentuximab vedotin, SGN-35) to treat Hodgkin’s lymphoma (HL) and systematic A successful ADC consists of a MAb - a versatile platform for anaplastic large-cell lymphoma (sALCL) (17). Adcetris anticancer therapy which is capable of binding to the surface of generated revenues of $34.5 million, for the first quarter of 2012 tumour cell-specific antigens (30). These antigens include (18). Another ADC success came in February 2013 when the over-expressed B-cell surface proteins in non-Hodgkin’s FDA announced the approval of Kadcyla (trastuzumab lymphoma (NHL) such as CD19, CD20, CD21, CD22, CD40, CD72, emtansine, T-DM1) for the treatment of metastatic breast CD79b and CD180, extending to the T-cell proteins CD25 and cancer (19). This ADC combines the blockbuster MAb CD30 of the immune system. Moreover, proteins that are over- Herceptin (trastuzumab) with an anti-mitotic maytansinoid drug expressed on carcinoma cells, including the human epidermal called DM1 (20). The projected annual sales for this particular growth factor receptor 2 (HER2); prostate-specific membrane ADC are in the region of US$2-5 billion (21). antigen (PSMA) and cryptic family protein 1 B (Cripto) are also To date, most of the cytotoxic drugs utilised in the development antigens. These tumour-associated antigens have been studied of ADCs (Table 1) are potent microtubule polymerisation as potential treatments for the following oncology indications: inhibitors (e.g. auristatins, maytansinoids, taxol); or DNA minor leukaemia, lymphoma and multiple myeloma (31). groove disruptors (e.g. calicheamicins, duocarmycins) (20) and The function of cytotoxic drugs (e.g. auristatins, maytansinoids topoisomerase II inhibitors (doxorubicins and camptothecins). and calicheamicins), are designed to induce tumour cell death, All the above cytotoxic drugs have shown to possess in vitro by causing irreversible DNA damage and/or interfering with the potency against various tumour cell lines in the 10-9-10-11 M mechanism of cell division (32). The theory behind the range compared to first generation ADCs using doxorubicin mechanism of action of ADCs (Figure 1) involves the following -7 (IC50 = 10 M) (22). The other emerging drug payloads include processes: Binding (Stage 1) - The MAb component of the ADC the sequence selective DNA alkylating agents called binds to the target antigen on the surface of the tumour cell to pyrrolobenzodiazepines (PBDs) (23). produce an ADC-antigen (ADC-CDX) complex, which is engulfed into a clathrin-coated vesicle; Clathrin-Mediated Endocytosis (Stage 2) - This binding then initiates a cascade of events, THERAPEUTIC ANTIBODIES involving the internalization of the ADC-antigen clathrin coated vesicle into the tumour cell. Consequently, the vesicle loses its Cancer cells contain a variety of surface antigens that can be coat and enables the ADC-antigen complex to fuse with an early utilised as biomarkers to differentiate tumour and non-tumour sorting endosome, to initiate the release of the antigen from the tissues (24). A number of MAbs have high binding specificity ADC. At this stage, the antigen may be recycled back to the cell towards tumour-specific antigens. This can induce antibody- membrane. Furthermore, the early endosome converts to a late dependent cell-mediated cytotoxicity (ADCC) and endosome containing the ADC; Degradation (Stage 3) - The complement-dependent cytotoxicity (CDC) by lyses of the internalized ADC is transported through the late endosome target cell, resulting in the blocking of signalling pathways (25). pathway to the intracellular compartment of a lysosome, where it Another function of the MAb is to provide a delivery vehicle to is degraded to release the cytotoxic drug. The cleavable linkers 31 transport the drug payload to a surface antigen on the tumour rely on processes inside the cell to liberate the cytotoxic drug cell, facilitating the internalization of the ADC. This initial work such as reduction of disulfide bonds mediated by glutathione with antibodies displayed high specificities and affinities for (GSH) in the cytoplasm, exposure to acidic conditions (pH ~4) in receptors that produced an overactive immune response (26). the lysosome, or cleavage by specific proteases within the cell. Today biopharmaceutical companies have addressed some of Conversely, non-cleavable linkers require
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