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Brentuximab Vedotin (SGN-35) CCR FOCUS Brentuximab Vedotin (SGN-35) Jessica Katz1, John E. Janik2, and Anas Younes3 Abstract Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization mono- methylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n ¼ 102) and 87% in patients with anaplastic large cell lymphoma (n ¼ 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed–Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration. Clin Cancer Res; 17(20); 6428–36. Ó2011 AACR. Introduction (Zevalin; Spectrum Pharmaceuticals) and 131I tositumo- mab (Bexxar; GlaxoSmithKline), for the treatment of Monoclonal antibodies have emerged as a major focus relapsed B-cell lymphoma (2–5). An alternative strategy, fordrugdevelopmentforcancertreatmentsinceritux- modification of antibodies to deliver chemotherapeutic imab and trastuzumab received approval in the late agents to tumors, required a more prolonged develop- 1990s. Rituximab, the first monoclonal antibody mental pathway to address the large number of factors approved for the treatment of cancer, produced regression that can affect the therapeutic efficacy of these molecules of lymphadenopathy in 50% of patients with relapsed (6–10). Gemtuzumab ozogamicin (Mylotarg; Pfizer) was follicular lymphoma (1). However, although they can the first antibody-drug conjugate (ADC) to be approved produce significant clinical benefits, particularly when forthetreatmentofcancer,butitwaswithdrawnfromthe administered with chemotherapy, monoclonal antibo- market in 2010 for lack of efficacy and increased patient dies alone do not produce long-lasting clinical benefit. deaths (11). Despite this setback, ADCs now appear Early attempts to improve the therapeutic efficacy of poised to play a major role in cancer treatment (12). monoclonal antibodies prompted the addition of linkers that allowed the conjugation of radioisotopes for deliv- CD30 Biology ering high doses of radiation to the site of the tumor. This strategy resulted in the U.S. Food and Drug Administra- CD30 is an attractive target for monoclonal antibody tion (FDA) approving 2 agents, ibritumomab tiuxetan therapy because of its limited expression on normal tissues and its uniform, high-level expression on malignant cells in patients with classical Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL; ref. 13). Expression of CD30 is Authors' Affiliations: 1Department of Hematology/Oncology, Lankenau associated with T-cell activation. In lymph nodes, it is Medical Center and Lankenau Institute of Medical Research, Wynnewood, Pennsylvania; 2Metabolism Branch, National Cancer Institute, Bethesda, expressed in the parafollicular areas, in the rim of the Maryland; and 3The University of Texas MD Anderson Cancer Center, follicular center, and on centroblasts within the germinal Houston, Texas centers (14). CD30-positive cells are also found in the Corresponding Author: John E. Janik, Route 206 and Province Line Road, medulla of the thymus. Both T and B cells may be positive Lawrenceville, NJ 08543; E-mail: [email protected] for CD30 expression, which is more commonly observed in doi: 10.1158/1078-0432.CCR-11-0488 proliferating cells. It has been reported that 3% to 31% Ó2011 American Association for Cancer Research. of peripheral blood lymphocytes, most of which are 6428 Clin Cancer Res; 17(20) October 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. SGN-35 CD8-positive and produce IFN-g and interleukin (IL)-4, below). The constitutive NF-kB activity associated with express CD30 (15). Other normal cells that express CD30 classical Hodgkin lymphoma prevents the apoptosis include macrophages, activated natural killer cells, endo- induced in ALCL. thelial cells, and decidual cells. Lymphoid cells infected with Epstein–Barr virus, human T-cell leukemia virus, or Antibody-Drug Conjugates Herpesvirus saimiri may express high levels of CD30. CD30 is a member of the TNF receptor (TNFR) super- ADCs combine the specificity of targeting inherent to family, which comprises more than 25 members, includ- monoclonal antibodies with the ability to deliver highly ing the TNF receptors Fas, CD40, and RANK (16, 17). A toxic chemotherapeutic agents that cannot be adminis- protein analysis of CD30 showed an 18-residue leader tered systemically. SGN-35 consists of the cAC10 mono- peptide followed by a 365-amino-acid extracytoplasmic clonal antibody (SGN30) modified by the addition of a domain, a 24-amino-acid transmembrane region, and a dipeptide linker to permit attachment of microtubule cytoplasmic tail of 188 amino acids (14). Signaling polymerization monomethylauristatin E (MMAE). The through the TNFR superfamily of molecules affects cel- protease-sensitive dipeptide linker is composed of citrul- lular proliferation, survival, and differentiation, and these line and valine. Two to 8 linkers are attached per molecule effects are mediated through the cytoplasmic domains of of cAC10 monoclonal antibody, with the most prevalent the receptors (18). TNFR1 and Fas contain an 80-amino- species containing 4 molecules. The advantage of the acid motif, designated the death domain, that induces dipeptide linker is that it provides maximal serum stabil- apoptosis through interaction with Fas-associated death ity with efficient hydrolysis and release of MMAE by domain (FADD) and TNFR-associated death domain human cathepsin B (Fig. 2A; ref. 19). The features that (TRADD), which in turn recruit caspases to initiate the determine the safety and efficacy of ADCs are described by apoptotic cascade. In contrast, TNFR1 can activate NF-kB Teicher and Chari (12) in their overview of ADCs in this to prevent cell death through the interaction of TNFR1, CCR Focus section. TRADD, and TNFR-associated factor 2 (TRAF2). CD30 Proteins are internalized by cells through phagocytosis, does not contain a death domain but is able to produce macropinocytosis, caveolae-mediated endocytosis, cla- an apoptotic stimulus. The mechanism for this effect is thrin-mediated endocytosis, and clathrin- and caveolin- thought to be related to the degradation of TRAF2, which independent endocytosis (20). Phagocytosis is restricted to prevents its interaction with the TNFR1-TRADD complex, specialized cell types, such as macrophages and neutrophils, thereby enhancing death signaling through the TNFR and has little role in ADC effects. Similarly, macropinocy- (Fig.1;ref.16).CD30ligandandmonoclonalantibodies tosis results in uptake of extracellular proteins in a concen- that interact with this signaling portion of the molecule tration-dependent fashion and, thus, would not provide are thought to induce apoptosis by initiating CD30 sig- significant therapeutic advantage compared with free naling without concurrent NF-kBactivation(discussed drugs. Both caveolae- and clathrin-mediated uptake have Figure 1. CD30 signaling. A, TRAF2 interacts with CD30 and TRADD bound to the cytoplasmic domain of TNFR1. TNFR1 signaling through TRADD and TRAF2 interaction produces a prosurvival signal through activation of NF-kB. B, ligation of CD30 results in TRAF2 degradation, depleting TRAF2 and making it unavailable to interact with TRADD. In the absence of TRAF2, NF-kB is not activated, and TNF signaling will preferentially activate apoptotic pathways. The constitutive activation of NF-kBin some cases of classical Hodgkin lymphoma may account for the lack of activity with SGN-30 alone. www.aacrjournals.org Clin Cancer Res; 17(20) October 15, 2011 6429 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. CCR FOCUS Figure 2. A, SGN-35 structure. MMAE is attached to the IgG1 monoclonal antibody cAC10 by sulfhydryl groups in cysteine residues. A mild reduction of the interchain disulfides is used to attach the citrulline-valine dipeptide linker. A variable number of drug molecules are attached, ranging from 2 to 8, with 4 being the most prevalent. B, ADC internalization process. SGN-35 is internalized following binding to cell surface CD30 by clathrin-mediated endocytosis. The clathrin-coated vesicle is uncoated to allow fusion with lysosomes, and clathrin recirculates to the cell surface. In the acidic milieu of the vesicle, cathepsin cleaves the citrulline-valine dipeptide
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