Therapeutic Monoclonal Antibodies for Cancer: the Past, Present, and Future

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Therapeutic Monoclonal Antibodies for Cancer: the Past, Present, and Future Current Topics Advances in Immuno- therapy Strategies Juntendo Medical Journal 2015. 61(6), 601-607 Therapeutic Monoclonal Antibodies for Cancer: The Past, Present, and Future KAZUNORI KATO*1) 2) *1)Atopy Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan, *2)Department of Biomedical Engineering, Graduate School of Science and Engineering, Toyo University, Tokyo, Japan Monoclonal antibodies (mAbs) for cancer therapy can be broadly divided into three classes. First are those that target biological features expressed by the tumor cell itself, second are those that target factors produced by the tumor cell or as a host response to the tumor, and third are those that target the immune regulatory networks responsible for inhibiting antitumor immune responses. Of these, tumor-specific therapeutic mAbs are particularly unique because they partially and passively reconstitute the humoral arm of the tumor antigen- specific immune response, as well as provide critical support in establishing the antigen-specific adaptive immune response through cross-priming. This review focuses on these categories and will discuss ongoing clinical trials. Key words: monoclonal antibody, HER2, immune checkpoint, PD-1, CTLA-4 Introduction Monoclonal antibodies target to tumor-specific antigens The commercial pipeline of monoclonal antibodies (mAbs) is highly dynamic, with a multitude of 1. Trastuzumab and pertuzumab target HER2/ transitions occurring during the year as product neupathway candidates advance through the clinical phase and Trastuzumab (Herceptin ®), a humanized mAb onto the market. Rituximab (anti-CD20) and specific for the human epidermal growth factor trastuzumab (anti-HER2), the first mAbs were receptor 2 (HER2/neu), is widely used to treat approved for cancer therapy. Then two mAbs were HER2-overexpressing breast cancers at every approved in use that target soluble host factors stages except ductal carcinomas that are negative involved in the antitumor response, bevacizumab for HER2 1). Trastuzumab was first approved in (anti-VEGF) and denosumab (anti-RANKL). 1998 and the second-generation mAb pertuzumab Recently, the application of therapeutic mAbs (PERJETA ®) was approved in 2012 as treatment ipilimumab (anti-CTLA-4) and nivolumab/pem- for metastatic breast cancer. It has also been brolizumab (anti-PD-1) that specifically target the approved for the treatment of HER2-positive nodal checkpoints for T-cell activation and effector metastatic adenocarcinoma of the stomach and function is a new area of increasing preclinical and gastroesophageal junction. Trastuzumab has been clinical investigation. The clinical developments of thought to function primarily by inhibiting signal mAbs in various categories are described and transduction via the cell surface HER2 receptor, but summarized in this review (Figure-1). it can also modulate tumor immunity through multiple mechanisms. It recruits innate immune effector cells such as natural killer cells and Kazunori Kato Atopy Research Center, Juntendo University Graduate School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan TEL: +81-3-5802-1045 E-mail: [email protected] 〔Received Dec. 14, 2015〕 601 Kato: Therapeutic monoclonal antibodies for cancer Blockade of growth Targeting tumor specific Inhibitor of immune factor and its receptor Ag & drug conjugate checkpoint molecule Therapeutic Antibodies Effectors Drugs Radioactive Treg Treg NK Treg Tumor Tumor Tumor Bevacizumab Trastuzumab Ipilimumab Ramucirumab Pertuzumab Nivolumab Denosumab Rituximab Pembrolizumab Cetuximab Ofatumumab Atezolizumab Panitumumab Ocrelizumab Bavituximab Tocilizumab Obinutuzumab Mogamulizumab Figure-1 The clinical antibodies in various therapeutic categories macrophages to the tumor microenvironment in nancies dependent on HER2-signaling. Two clinical order to facilitate antibody-dependent cellular trial of trastuzumab combined with vaccination cytotoxicity (ADCC). Trastuzumab can also induce have been reported. In one study, a HER2-specific the ubiquitination and degradation of internalized T-helper peptide vaccine was combined with stan- HER2 proteins, thereby increasing proteasome- dard trastuzumab therapy regimen in 22 patients dependent antigen presentation on MHC mole- with metastatic breast cancer 6). This study demon- cules 2). Accordingly, it augments the cytotoxic strated the safety of the combination, with about activity of HLA Class I-restricted HER2-specific 15% of patients displaying an asymptomatic decline cytotoxic T lymphocytes (CTLs) against HER2- in cardiac ejection fraction. Immune responses positive breast cancers. In HER2-transgenic mice against HER2 and other tumor-associated antigens study, HER2 mAb therapy alone induced new were observed and the magnitude of the immune CD8-positive CTLs that break immune tolerance 3). response was inversely correlated with serum In humans, a single dose of trastuzumab induced TGF-beta levels, indicating the promotion immune apoptosis in primary tumors within 24 hours, and modulating effect by the treatment with trastuzu- trastuzumab-based neoadjuvant chemotherapy is mab. In the second, the combination with trastuzu- associated with the development of T-bet-positive mab, cyclophosphamide and GM-CSF-secreting lymphoid nodules in patients with locally advanced breast cancer cell-based vaccine achieved an overall breast cancer. Importantly, these lymphoid nodules survival 40 months compared to the historical overall are also associated with enhanced overall survival 4). survival (OS) of 13-24 months in similar patients Finally, chemotherapy combined with trastuzumab who received standard trastuzumab alone 7). These has been associated with the development of HER2- clinical data strongly argues for the establishment of specific CD4-positive T cell responses in patients combination immunotherapy incorporating trastu- with both early and metastatic breast cancers. zumab and other immune modulators such as The combination of low-dose cyclophosphamide, cyclophosphamide or immune checkpoint inhibitors anti-HER2 mAb and HER2-specific peptide vacci- in patients with HER2-positive cancers. nation generated the highest numbers of HER2- specific CTLs, and protected up to 70% of neu-N 2. Antibody-drug conjugate of trastuzumab transgenic mice from the outgrowth of established Antibody-drug conjugates (ADCs) are becoming tumors 5). These observations provide strong sup- an increasingly important sub-class of antibody- port for testing trastuzumab in combination with related therapeutics. Trastuzumab emtansine HER2 targeted vaccination inpatients with malig- (Kadcyle ®) were recently approved for marketing 602 Juntendo Medical Journal 61(6), 2015 Therapeutic mAbs to HER2 Rituximab therapy is known to result in profound ①Trastuzumab B-cell depletion. B cells have been shown to inhibit (HERCEPTIN) tumor-specific CTL induction, suggesting that ②Pertuzumab (PERJETA) B-cell depletion in the setting of rituximab therapy ③ ③Trastuzumab with emtansine may not inhibit, and could enhance, vaccine- (KADCYLA) induced tumor immunity. Based on this idea, ① ② several preclinical and clinical trials of rituximab combined with adaptive immunotherapy against B-cell malignancies have been demonstrated 12) 13). Additionally, rituximab has been indicated for the treatment of rheumatoid arthritis (RA) with another prescription medicine called methotrexate, to reduce the signs and symptoms of moderate to HER2(erbB2) HER3(erbB3) severe active RA in adults, after treatment with at least one other medicine called tumor necrosis HER2/HER3 heterodimer induces cell growth signal factor (TNF) antagonist has been used. Thera- peutic use of rituximab for the treatment of RA is Figure-2 Three clinical antibodies to HER2/erbB2 approved only by FDA and EMA but not by MHLW-PMDA in Japan so far. In recent years, new generations of anti-CD20 both by the US Food and Drug Administration monoclonal antibodies (mAbs) have been devel- (FDA), European Medicines Agency (EMA) and oped for potential benefits over the classical, the Japanese Ministry of Health, Labour and first-generation mAb rituximab. These sec- Welfare and Pharmaceuticals and Medical Devices ond-generation mAbs, which include ofatumumab, Agency (MHLW-PMDA) as a treatment for veltuzumab, and ocrelizumab, are humanized or human HER2-positive breast cancer 8). Kadcyle is fully human to reduce immunogenicity, but with an an ADC comprising trastuzumab linked to Immu- unmodified Fc region 14)-16). Ofatumumab is a fully noGenʼ s DM1 maytansinoid drug. One of major human anti-CD20 IgG1 mAb in clinical develop- pharmaceutical company Roche entered into licens- ment for hematological malignancies and autoim- ing agreements with ImmunoGen giving rights to mune diseases. Ofatumumab specifically recognizes use ADC technology to develop therapeutics for an epitope encompassing both the small and large specific targets. It is currently also undergoing extracellular loops of CD20 molecule, and is more evaluation in various clinical Phase trials comparing effective than rituximab at CDC induction and efficacies and overall survival to trastuzumab and killing target cells. Veltuzumab is a humanized taxane as standard regimen. anti-CD20 mAb with complementarity-determin- ing regions similar to rituximab. This antibody has 3. Rituximab and other mAbs target CD20 enhanced binding avidities and a stronger effect on Rituximab (Rituxan ®), a chimeric mAb specific CDC compared with rituximab. Ocrelizumab is a for the cell surface molecule
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