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 - 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: , HER2, immune checkpoint, PD-1, CTLA-4

Introduction Monoclonal antibodies target to tumor-specific The commercial pipeline of monoclonal antibodies (mAbs) is highly dynamic, with a multitude of 1. and 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. (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, 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 (anti-CTLA-4) and /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 Pertuzumab Nivolumab Denosumab Rituximab Ocrelizumab Bavituximab Tocilizumab 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 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

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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 , 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 CD20 expressed by humanized mAb with the potential for enhanced normal B cells and over 95% of B-cell leukemia and efficacy in lymphoid malignancies compared with lymphoma, is widely used both as a single agent and rituximab due to increased binding affinity for the combined with chemotherapy and radiation 9). low-affinity variants of the FcγRIIIa receptor. Although the primary mechanism of action remains Ocrelizumab is undergoing phase III clinical trials unclear, it has been shown to mediate ADCC, for rheumatoid arthritis and lupus nephritis, promote apoptosis, and enhance cross-priming of however, these has been discontinued the adaptive immune response 10). Rituximab modu- because of several adverse reactions at 2010. late src signaling in follicular lymphoma cells, The third-generation mAbs are also humanized leading to lower levels of active STAT-3 and bcl-2 mAbs, but in addition they have an engineered Fc and increased sensitivity to chemotherapy 11). to increase their binding affinity for the FcγRIIIa

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receptor. One of anti-CD20 mAb, obinutuzumab, is and almost half displayed some decrease in PSA a fully humanized, type II, IgG1 mAb derived from from baseline, indicating that blocking of VEGF humanization of the parental B-Ly1 mouse anti- would be useful for the adjuvant immunotherapy. body and subsequent glycoengineering using In order to inhibit VEGF/VEGFR interaction, GlycoMab ® technology. Obinutuzumab was design- several monoclonal antibodies specific for VEGF ed for enhanced ADCC and superior direct cell- receptors have been developed. Tumor-bearing killing properties, in comparison with currently nontolerate mice treated with a specific for VEGF available type I antibodies 17). These kinds of mAbs receptor-2 (VEGFR2) develop HER2-specific T having an engineered Fc to increase their binding cells, even in the absence of vaccination 21).Inthe affinity for the FcγRIIIa receptor will be commonly setting of antigen-specific immune tolerance, used for the treatment of not only B-cell leukemia/ sequencing vaccination with cyclophosphamide and lymphoma but also nonhematological malignancies. doxorubicin in the setting of treatment with VEGFR2 mAb unmasks the T-cell dependent- Monoclonal antibodies target to tumor activity of the VEGFR2 mAb and allows the vaccine microenvironment factors to work, resulting in a tumor-free survival rate of about 70%. Based on these findings, ramucirumab 1. Bevacizumab and Ramucirumab to VEGF/ (Cyramza ®) was approved by FDA in 2014. VEGFR interaction Ramucirumab that targets human VEGFR2 is Bevacizumab is a chimeric, partially humanized indicated for the treatment of advanced gastric mAb specific for the vascular endothelial growth cancer or gastro-esophageal junction adenocarci- factor (VEGF), a cytokine critical for tumor- noma, as a single-agent after prior fluoropyrimi- associated angiogenesis. It is currently approved for dine- or platinum-containing therapy. Currently, treating colorectal cancers, glioblastomas, non- ramucirumab is undergoing regulatory review by small cell lung carcinomas, and renal cell carcino- EMA for treating gastric cancer and hepatocellular mas. In addition to promoting neo-vessel formation, carcinoma, and also evaluation in clinical Phase III VEGF inhibits T cell developments and dendritic studies in patients with non-small cell lung cells differentiation, leading to tumor-related carcinoma, colorectal cancer and breast cancer. immune suppression in cancer patients. Monoclonal antibody specific for VEGF can improve the 2. Denosumab specific for RANKL numbers and function of dendritic cells in tumor- Denosumab is a mAb recently approved for the bearing mice, thereby potentiating dendritic cell- management of malignant bone disease in multiple based immune therapy 18). Bevacizumab therapy myeloma or breast cancer; it is also used to prevent can increase the B- and T-cell subsets in cancer fragility fractures in osteoporosis 22). This mAb is patients, and augment the ability of dendritic cells specific for the signaling pathway controlled by the derived from cancer patients to stimulate T-cell interactions of receptor activator of NF-kappa-B responses to recall antigens. Importantly, blockades ligand (RANKL) and its antagonist osteoprote- of VEGF/VEGF receptor (VEGFR) pathways can gerin. RANKL is expressed at high levels by acti- decrease macrophage and myeloid-derived sup- vated T cells, and its receptor RANK is expressed pressor cell (MDSC) infiltrating tumor tissues 19). by monocytes, macrophages and dendritic cells. To In addition, the efficacy of adoptive cellular therapy date, the FDA approved denosumab to prevent would be synergistically enhanced by VEGF mAb skeletal-related events (SREs) associated with promoting the infiltration of transferred T cells into metastatic solid tumors. tumor 20). To date, one clinical trial combining bevacizumab and a cancer vaccine has been Monoclonal antibodies target to immune reported. Patients with metastatic prostate cancer checkpoints in biochemical relapse were treated with a combina- tion of prostatic acid phosphatase (PAP) -pulsed Recently, it has been reported various molecules antigen presenting cells (APCs) and bevacizumab. contributed to immune checkpoint pathways in All patients developed immune responses to PAP lymphocyte activation and differentiation. T cells

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that recognize the cognate antigen may also preclinical activity seen in mouse models. Both express a number of molecules on their surface, ipilimumab and tremelimumab, fully human anti- such as CTLA-4, PD-1, LAG-3, and BTLA. These bodies against CTLA-4, have been most widely molecules serve as checkpoints, controlling the tested in patients with metastatic , where quality and magnitude of a T-cell response. In durable clinical responses have been well docu- normal circumstance, these checkpoints would act mented 24)-26). The promising results seen in Phase II to protect the host from an overactive immune studies led to Phase III evaluation. Several Phase III reactions and autoimmunity. In case of cancer, studies were performed and the survival benefit of blockade therapy of these checkpoints could help ipilimumab was confirmed in a subsequent random- break tolerance and could serve as to help maintain ized Phase III trial 27). OS was significantly longer a high quality long-lasting T-cell response. The for patients who received dacarbazine with ipilimu- first T-cell immune checkpoint targeted for anti- mab (11.2 mo.) than patients with dacarbazine body blockade was CTLA-4 and then PD-1. In this with placebo (9.2 mo.). Based on OS in Phase III chapter, the preclinical studies and clinical benefits studies, FDA approved ipilimumab for the treat- of therapeutic mAbs to CTLA-4, PD-1 and PD-L1 ment of patients with unresectable or metastatic are introduced. melanoma in 2011. Another Phase III study of tremelimumab was halted after an interim anal- 1. CTLA-4 blockade ysis failed to demonstrate a benefit. Expectedly, Cytotoxic T-lymphocyte antigen 4 (CTLA-4; immune-related adverse effect such as colitis, CD152) is a negative regulator of T-cell function, dermatitis, hepatitis and endocrinopathies were and antibodies have been developed which inhibit observed in patients treated with ipilimumab 28).To this important immunologic checkpoint. In preclini- date, a number of combination strategies of ipilimu- cal studies, CTLA-4 blocking antibodies were able mab with novel immunotherapies or molecularly to induce potent antitumor immunity and provided targeted therapies are likely to be promising based rationale for clinical use. Ipilimumab (Yervoy) a upon have been explored in clinical trials. At IgG1 mAb against CTLA-4 and was the first drug present, ipilimumab is being tested in combination to demonstrate an overall survival benefit for with antibody to PD-1 (Nivolumab) for patients patients with melanoma in clinical Phase III trial 23). with NSCLC. Tremelimumab is an IgG2 antibody with a plasma long half-life of approximately 3 weeks. 2. PD-1 and PD-L1 blockade The clinical development of ipilimumab was built Several other checkpoint molecules are up-regu- upon a foundation of basic research into the lated after the T cell and antigen-presenting cell mechanisms that regulate T-cell activation. The (T/APC) interaction. These molecules help limit “two signal” model of T-cell activation was the the T-cell response once the cells begin to migrate product of fundamental studies performed in the to tissue. This is believed to be a means of 1970s and 1980s. In this model, antigen-specific maintaining peripheral tolerance. One of important T-cell activation requires both T-cell receptor molecules, programmed cell death-1 (PD-1) is engagement (signal 1) and a co-stimulatory signal expressed by chronically activated CD4 and CD8 T (signal 2) for fully function, this hypothesis has cells 29). PD-1 is also significantly up-regulated on T been validated and expanded in the 2000s. It is now cells present in cancerous tissues in various tumor clear that a diversity of co-stimulatory and co- types, including melanoma, prostate cancer 30). The inhibitory molecules are required to both promote PD-1-positive tumor-infiltrating T cells (TILs) and regulate the complex process of T-cell activa- exhibit an exhausted phenotype with impaired tion. Especially, CTLA-4 plays a fundamental role effector function compared with PD-1-negative as an inhibitory receptor, or checkpoint, in the TILs and PBLs. When PD-1 binds its ligand PD-L1 process of T-cell activation, such as proliferation, (B7-H1) or PD-L2 (B7-H2), cytokine production cytokine production and differentiation. and T-cell activation are diminished 31). This As shown previously, CTLA-4 blocking antibody inhibitory mechanism is present to help prevent therapy in humans was developed based on the peripheral autoimmunity. In case of tumor toler-

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ance, PD-1 antibody blockade may serve as a cell membrane and known as “Eat-me-signal” means to maintain a high level of T-cell response molecule that is recognized by phagocytes. After post DC vaccination. the irradiation or treatment of anti-cancer drugs, Two blocking monoclonal antibodies to PD-1 PS is reversed to express outside of cell membrane were just approved for clinical use in 2014 by FDA. of various tumor cells and endothelial cells 32). During clinical phase studies, several drastic Bavituximab, chimeric IgG1 mAb, was given US antitumor effects including primary and metastatic Fast Track designation of NSCLC. The clinical tumor sizes and overall survival were observed. Phase III study of bavituximab plus docetaxel vs. Unexpectedly, the dose escalation trial showed a docetaxel alone in patients with late-stage non- very low incidence of adverse events such as colitis, squamous NSCLC began recruiting patients in 2013. with only rare grade III toxicities. These autoim- Another target molecule related in immune mune adverse events appeared to be significantly checkpoint is the lymphocyte activating gene-3 less than those noted with ipilimumab (anti- (LAG-3) 33). Antibody specific to LAG-3 was CTLA-4 blockade). designed and generated by Bristol-Myers Squibb. Nivolumab (Opdivo) was first approved to use The purpose of this study is to characterize the for the treatment of melanoma in US and has safety, tolerability, dose limiting toxicities and orphan drug designation in Japan. Recently, FDA maximum tolerated dose of BMS-986016 (code has granted nivolumab Breakthrough Therapy number of anti-LAG3) administered to subjects designation for the treatment of patients with with relapsed or refractory chronic lymphocytic Hodgkin lymphoma (HL) after failure of autologous leukemia (CLL), lymphomas and multiple myeloma stem cell transplant and brentuximab. In addition, (MM), and Phase I trial just began to recruit various clinical settings in Phase III trials are patients with CLL. undergoing of patients with non-small cell lung carcinoma, renal cell carcinoma and head and Summary neck squamous carcinomas. Another candidate of PD-1 mAb, pembrolizumab (Keytruda), was also Antibody therapeutics are generally recognized approved in 2014 for unresectable or metastatic as having higher phase transition rates compared melanoma and is undergoing evaluation in a Phase with small molecules drugs, but nonetheless discon- III study of patients with NSCLC. tinuations do occur. The development of biological Additionally, therapeutic mAb specific for the drugs such as therapeutic antibodies is a time- ligand of PD-1 (termed PD-L1 or B7-H1) is consuming, risky business. Canonical therapeutics undergoing evaluation in Phase III clinical trial as antibodies such as tumor-targeting antibodies, treatment for NSCLC by Genentech/Roche. An which are the majority of clinical approved anti- Fc-engineering anti-PD-L1 mAb, MPDL3280A, bodies, thus have less approval success rate of 23% has been compared with docetaxel in patients with compared with those for antibody-drug conjugates locally advanced or metastatic NSCLC who have (ADCs) of 35%. The success rate will be increased failed platinum therapy. Another PD-L1 mAb by novel techniques of the antibody engineering MED14736 contains three mutations in Fc portion and cultivation of a better understanding of that abrogates Fc-mediated effector function. After biological functions of both target molecules and review and approval, these mAbs will be delivered therapeutic antibodies in the future. in clinical setting soon. References 3. New candidates of immune checkpoint inhibitor Base on the success of PD-1 and CTLA-4 mAbs, 1) Vogel CI, Cobleigh MA, Tripathy D, et al: Efficacy and several new mAb candidates have entered clinical safety of trastuzumab as a single agents in first-line treatment of HER2-overexpressing metastatic breast phase studies. One of promising therapeutic mAb, cancer. J Clin Oncol, 2002; 20: 719-726. bavituximab, which recognize phosphatidyl-serine 2) Varchetta S, Gibelli N, Oliviero B, et al: Elements related (PS) on tumor cells and endothelial cells in tumor to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary microenvironments. PS is normally expressed inner

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