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Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins

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Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Drug Discovery, 2014, 9, 35-65 35 Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins Franco Dosio1,*, Barbara Stella1, Sofia Cerioni1, Daniela Gastaldi2 and Silvia Arpicco1 1Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, I-10125, Italy; 2Dipartimento di Bio- tecnologie Molecolari e Scienze per la Salute, University of Torino, Torino, I-10125, Italy Received: December 13, 2012; Accepted: February 21, 2013; Revised: March 7, 2013 Abstract: Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These bio- pharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined. Keywords: Antibody drug conjugate, anticancer agents, auristatins immunotoxin, calicheamicins, cross-linkers, duocarmycins, maytansinoids. 1. INTRODUCTION [2]. Immunoconjugates have evolved over 40 years; with antibody-drug conjugates (ADCs) they recently reached sig- Monoclonal antibodies (mAbs) are eminently suitable as nificant clinical and regulatory milestones, with the market- drug carriers, thanks to their selectivity and flexibility. The ing approval of brentuximab vedotin. Molecular engineering recent successful development of monoclonal antibodies that techniques have also had a significant impact on the effi- target key components of biological pathways has expanded cacy/toxicity profiles of immunotoxins (ITs), for example the range of treatment options for patients with several can- denileukin diftitox, which is now registered for the treatment cers. of cutaneous T-cell lymphomas. Antibody-based therapeutics are of growing significance This review will provide an overview of the more ad- in cancer therapy, as is shown by the fact that 33 such formu- vanced ADCs and ITs in the industrial pipeline, or under lations (in the form of a mAb as such or conjugated with a development in academic research laboratories. The mecha- drug) have now been approved for oncologic indications by nisms underlying cell intoxication by toxins or by anticancer the FDA and are marketed in the USA. Eight of these had drugs will first be presented, followed by the evolution of the global market revenues above US $1 billion, and their com- structure of conjugates obtained by molecular biology or bined global revenues exceeded US $50 billion. These thera- chemical synthesis. On the basis of the targeting agent em- peutics are one of the fastest growing sectors in the pharma- ployed, the conjugates will be divided into two major ceutical industry. The commercial pipeline of mAb-based groups: those targeting hematologic and those targeting solid therapeutics is still growing, and nearly 350 candidates [1], cancers. Finally, the most advanced results obtained in pre- not only for oncological use, but also for several immu- clinical or clinical trials will be described in some detail. Due nological indications and for Alzheimer’s disease, are now in to the impressive body of basic research in the field of ADCs clinical development. Progress in the development of anti- and ITs, the review will concentrate chiefly on patented ap- body-based therapeutics is dramatically accelerating. proaches. Further, the traditional bivalent, monospecific, full-length Immunotoxins are protein-based therapeutics consisting IgG molecule only accounts for about half of the anticancer of a targeting moiety linked or fused to a killing moiety. The mAbs in the pipeline. The rest are compounds that can be target moiety can be an antibody or a ligand directed against conjugated to drugs, toxins or radiolabels; they may be mul- a receptor or cell-surface antigen that is specific for the tar- tispecific or otherwise engineered for increased functionality geted disease, while the active moiety is a member of a class of highly toxic proteins or enzymes. Essentially, any mole- *Address correspondence to this author at the Dipartimento di Scienza e cule that induces cell death by directly interfering with the Tecnologia del Farmaco, University of Torino, v. P. Giuria 9, I-10125 cell machinery, by modifying the cell membrane, or by in- Torino, Italy; Tel: +390116707082; Fax: +390112367697; ducing apoptotic proteins can be used. Because of the enzy- E-mail [email protected] 2212-3970/14 $100.00+.00 © 2014 Bentham Science Publishers 36 Recent Patents on Anti-Cancer Drug Discovery, 2014, Vol. 9, No. 1 Dosio et al. matic potency of these proteins, a small number of toxin conjugation strategies and their potential consequences for molecules successfully delivered to the cytoplasm (or to the obtaining potent and specific ADCs. ribosomal compartment) may be lethal to the cell [3]. Initially, ITs comprised mAb or growth factors chemi- 2. IMMUNOTOXINS cally conjugated to cytotoxic plant or bacterial toxins [4], but This section comprises a brief description of the toxin, these have largely been replaced by recombinant methods, followed by a detailed description of the applications of im- thanks to their considerable design flexibility and product munoconjugates/chimeric proteins that have reached ad- homogeneity. vanced clinical trials. The mAb moiety and receptor used to Monoclonal antibody technology is now mature, fully target the payload will be described, classifying ITs against humanized mAbs are in therapeutic use, and fragments of hematologic cancers and those targeting solid cancers. This varying complexity are available. Thus the most strenuous will be followed by data related to the most recent IT-related and continuous efforts are directed to manipulating the kill- approaches reported in the literature and protected by pat- ing moiety, where the success of delivering the cytotoxic ents. domain of an IT to the cell cytoplasm depends on a series of Basically, toxins contain a binding domain, a catalytic steps, each having varying degrees of efficiency depending domain, and, in some cases, a domain responsible for trans- on the cell type, antigen density, binding affinity, internaliza- location. Plants and fungi produce a number of molecules tion/recycling, and subcellular trafficking or endosomal es- with defensive functions, to protect themselves against cape. High anticancer activity is unfortunately usually con- pathogens. These proteins include ribosome-inactivating trasted by critical drawbacks, which are caused by varying proteins, which are capable of inactivating ribosomes by degrees of nonspecific toxicity, mainly affecting hepato- preventing attachment of elongation factors 1 and 2 to ribo- cytes, the kidneys and the vascular endothelium [5]. somal RNA, conversely, bacterial toxins inactivate elonga- ADCs are designed to specifically transport small mole- tion factor-2 (EF-2) by ADP ribosylation. These toxins have cules after appropriate chemical modification. The payloads been widely studied and are the subject of numerous reports. most frequently used for conjugation to the mAb include The most extensively-examined constructs comprise bacte- tubulin inhibitors, DNA double-strand break-inducing com- rial toxins, such as Pseudomonas exotoxin (PE) and diphthe- pounds, and DNA minor groove binder/alkylators, the major- ria toxin (DT), as well as the plant-derived deglycosylated ity of these were originally derived from natural products, ricin A chain (dgA) and recombinant gelonin (rGel). Other are now prepared by synthesis. Conceptually, ADCs act as more recent constructs, based on non-toxic Ribonuclease prodrugs minimizing the systemic toxicity of the free drug (RNases) of animal origin or proapoptotic endogenous pro- and augmenting the antitumor activity of the targeting vehi- teins, of human origin, have been proposed to induce effec- cle. This review will discuss the various parameters affecting tive cell death [6]. The diagram in Fig. (1) illustrates the Fig. (1). Immunotoxin endocytosis and trafficking within mammalian cells (modified from [7]). Advances in Antibody-Drug Conjugates and Immunotoxins Recent Patents on Anti-Cancer Drug Discovery, 2014, Vol. 9, No. 1 37 Table 1. Immunotoxins in Clinical Development. IT Targeting Moiety Target Indication Phase Toxin References Denileukin diftitox IL-2 IL-2R CTCL, T-CLL, B-CLL 2008 approved DT [80-84] (Ontak®) NHL, melanoma BL22 Murine anti-CD22 CD22 HCL, B-CLL, NHL, ALL Phase I, II PE [12, 13] dsFv fragment Moxetumomab Murine anti-CD22 CD22 HCL, B-CLL, NHL Phase I, II PE [14-18] pasudodotox dsFv fragment LMB-2 Murine anti-CD25 CD25 HCL, leukemia Phase II PE [30,31] scFv fragment SS1P
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