The developing trend of monoclonal antibodies in the treatment of colorectal cancer

Monoclonal antibodies (mAbs) against growth factors, receptors and tumor-specific/tumor-selective antigens represent a rapidly growing class of pharmaceutical agents which are poised to make a major impact on the treatment of colorectal cancer. mAbs targeting the epidermal growth factor receptor and the vascular endothelial growth factor have already been approved for the treatment of metastatic colorectal cancer. Other antibodies to the same and other molecular targets implicated in tumor growth and metastasis are undergoing intense preclinical and clinical evaluation. In both the neoadjuvant and adjuvant clinical settings, although mAbs are typically administered in combination with established cytotoxic chemotherapy regimens given their synergistic effect, several agents have demonstrated efficacy when given as monotherapy. At the same time, combination therapies with multiple targeted biological agents are actively being investigated. Existing clinical data and recent progress in preclinical and clinical studies of mAbs are reviewed.     

Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.     

Recent advances in the HER2 targeted therapy of gastric cancer

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2(HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancerresistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.     

Gefitinib: current and future status in cancer therapy

The epidermal growth factor receptor (EGFR) is recognized as a key modulator of tumor cell function and is considered to be a viable drug target in a range of solid malignancies. Current knowledge of its role in tumor growth and progression has led to a newly active area of anticancer research, investigating agents that target the activity of this receptor. Of these agents, gefitinib is furthest in clinical development, having received regulatory approval in Japan in 2002, and in the United States and Australia in 2003. Gefitinib is an orally active, EGFR-tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. A plethora of preclinical studies have suggested promising outcomes for this agent and have led to ongoing clinical trials in a wide range of tumors, including non-small-cell lung, head and neck, colorectal, prostate, and breast, either as monotherapy or in combination with standard chemotherapy, hormonal therapy, or radiotherapy. Furthermore, as biologic agents are specifically designed to attack different pathways of tumor growth and progression, the potential for the combination of gefitinib with other agents, given either concurrently or sequentially, to prevent or delay disease recurrence is also being investigated. This article provides a detailed overview of gefitinib, the rationale for its use in a wide range of tumor types, and the current clinical development status of this novel agent.     

Biologic therapy for colon cancer

Targeted biologic therapy remains a very active and evolving field since the US Food and Drug Administration approved cetuximab, a recombinant, human/mouse chimeric monoclonal antibody against the endothelial growth factor receptor, and bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, for the treatment of colorectal cancer. Benefits of these reagents in diverse clinic settings combined with different chemotherapeutic agents are being defined. Current research is focused on defining which patients will benefit from these treatments and how best to use them in the clinic. Additional preclinical and clinical studies will enable better usage of these biologic agents and lead to the development of new targeted therapies for the treatment of colon cancer.     

Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies

Several new agents that target the vascular endothelial growth factor (VEGF) pathway and inhibit angiogenesis are emerging as promising therapies in multiple cancer types. Bevacizumab, a humanized monoclonal antibody to VEGF-A, is currently approved in combination with intravenous 5-fluorouracil-containing regimens for the first-line treatment of metastatic colorectal cancer and recently demonstrated clinically important results in combination with chemotherapy in patients with non-small cell lung cancer and metastatic breast cancer. Other anti-VEGF agents that have shown benefit in various cancer types will be discussed in this monograph. Despite the often striking results observed with anti-VEGF agents, several unanswered questions remain, such as the optimal duration of therapy and patient selection criteria. These other issues, including the biologic rationale for anti-VEGF therapy, as well as recent clinical trial data with anti-VEGF agents in colorectal, pancreatic, lung, kidney, and brease cancers, are discussed.     

Angiogenesis inhibition in the treatment of colorectal cancer Part 3 of a 3-part series: targeting VEGF--current and future research directions

Treatment options for advanced colorectal have improved substantially in recent years as a number of agents have been developed that have different targets and mechanisms of action. Significant improvements in outcomes have been observed by combining multiple chemotherapeutic agents instead of the single-agent approach. Some debate still remains regarding which combination is most effective and in what order regimens should be given. In addition to cytotoxic chemotherapy drugs, targeted biologic agents have been developed to inhibit tumor angiogenesis, which may hamper the viability of the tumor. There may also be a synergistic effect between antiangiogenic agents and chemotherapy. Regulation of tumor angiogenesis may actually improve blood flow throughout the tumor, which could enhance delivery of chemotherapy through the circulation. One antiangiogenic agent currently approved for the treatment of advanced colorectal cancer is bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, a ligand known to be important for angiogenesis. The other currently approved biologic agent, cetuximab, targets the epidermal growth factor receptor. The combination of bevacizumab plus cetuximab has a biologic rationale. Randomized trials incorporating combination chemotherapy regimens plus both bevacizumab and cetuximab are currently underway, as are preliminary studies withnovel angiogenesis inhibitors.     

Integration of molecular targeted therapy with radiation in head and neck cancer

Approximately 600,000 new cases of head and neck cancer arise worldwide each year. Of these, a large majority are head and neck squamous cell carcinomas (HNSCC). Conventional treatments, including surgical excision followed by radiation and/or chemoradiotherapy have limited efficacy and are associated with substantial toxicity. To date, key targets for molecular targeted therapy in HNSCC are epidermal growth factor receptors and angiogenesis-related factors. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) and it is the only targeted therapy approved by the United States Food and Drug Administration for the treatment of HNSCC. Cetuximab in combination with radiotherapy represents a standard approach for newly diagnosed patients who are unable to tolerate platinum chemotherapy. Despite efficacy in preclinical HNSCC models, cetuximab is only effective in a subset of HNSCC patients, most likely due to the high heterogeneity of this cancer. Additional targets under active investigation include the PI3K/Akt pathway, the Ras-MAPK-ERK pathway and the JAK/STAT pathway, among others. Combining molecular targeted therapies and radiation may allow for deintensification of radiotherapy thereby reducing radiation toxicities and improving treatment outcomes. Here we review the preclinical and clinical data in support of treatment strategies that combined targeted therapy with radiation in HNSCC.     

Anti-EGFR and antiangiogenic monoclonal antibodies in metastatic non-small-cell lung cancer

ABSTRACT

Introduction: In recent years, several clinical trials have evaluated the efficacy and safety of biological therapies in lung cancer. Epidermal growth factor receptor (EGFR) and the axis vascular endothelial growth factor receptor (VEGF/VEGFR) are targeted by small molecules and monoclonal antibodies (mAbs), especially in non-squamous non-small-cell lung cancer (NSCLC).

Areas covered: The current state of the art of anti-EGFR and antiangiogenic monoclonal antibodies in metastatic NSCLC is reviewed and discussed.

Expert opinion: Bevacizumab and cetuximab are the most studied mAbs in NSCLC, but only bevacizumab is in clinical practice in the first-line setting. Necitumumab is a new anti-EGFR monoclonal antibody that improves survival when combined to cisplatin/gemcitabine chemotherapy and has been approved in first-line advanced NSCLC. Ramucirumab, an antiangiogenic drug binding with high affinity to VEGFR-2, improves the results of chemotherapy alone when administered with docetaxel and has been approved in second-line setting. Moreover, the novel combination of bevacizumab and erlotinib is very promising for the treatment of patients with NSCLC harbouring EGFR mutations. The association of antiangiogenic mAbs and immunotherapy is under investigation too.     

Molecular Ultrasound Imaging Using Contrast Agents Targeting Endoglin,Vascular Endothelial Growth Factor Receptor 2 and Integrin

Expression levels of endoglin, αv integrin and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated using targeted, contrast-enhanced ultrasonography in murine melanoma tumor models. Microvasculature and expression levels of biomarkers were investigated using specific contrast agents conjugated with biotinylated monoclonal antibodies. Ultrasound signal intensity from bound contrast agents was evaluated in two groups of mice: control mice and mice treated with sorafenib. Expression levels were analyzed by immunohistochemistry. Endoglin biomarkers were more highly expressed than αv integrin and VEGFR2. Endoglin decreased in the sorafenib group, whereas it tended to increase with time in the control group. Targeted ultrasound contrast agents may be used for non-invasive longitudinal evaluation of tumor angiogenesis during tumor growth or therapeutic treatment in preclinical studies. Endoglin protein, which plays an important role in angiogenesis, seems to be a target of interest for detection of cancer and for prediction of therapeutic efficacy.     

Recent developments in colorectal cancer treatment by monoclonal antibodies

A growing understanding of the molecular mechanisms involved in cancer biology and continuous refinement of available technologies for drug discovery have prompted the development of new therapeutic tools targeting specific cancer-associated molecular pathways. Among these so-called biological therapies, monoclonal antibodies have now reached the time of clinical application. Besides initial development of the murine antibody edrecolomab, the impact of monoclonal antibodies on cancer therapy has recently been clearly demonstrated in colorectal cancer by targeting two major pathways critical to tumourigenesis: the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signalling pathways. These antibodies showed significant clinical activity in advanced colorectal cancer, especially when combined with chemotherapy. This paper reviews the status of the monoclonal chimeric antibody cetuximab (Erbitux) and other anti-EGFR antibodies, and of bevacizumab (Avastin; an anti-VEGF humanised monoclonal antibody), in colorectal cancer treatment.     

Monoclonal antibodies for the treatment of osteoarthritis

ABSTRACT

Introduction: Osteoarthritis (OA) is a multifactorial chronic joint disease, and so far, there are no approved disease-modifying anti-OA drugs (DMOADs). There is an urgent need to develop therapies for different phenotypes of OA. Monoclonal antibodies (mAb) may slow structural progression, control inflammation and relieve pain, and thus have the potential to be DMOADs.

Areas covered: In this review, the authors searched the literature on PubMed, EMBASE and the Cochrane Library using keywords, including mAbs, biological agents, OA and osteoarthritis, electronically up to May 2016. They also included abstracts of international conferences. Furthermore, they reviewed experimental and clinical studies of various mAbs targeting different pathological mechanisms of OA, including ADAMTS, Interleukine-1, tumour necrosis factor, never growth factor and vascular endothelial growth factor.

Expert opinion: MAbs for the treatment of OA are under intense investigation and the results for some mAbs (e.g., anti-nerve growth factor mAbs, anti- vascular endothelial growth factor mAbs) are promising. The authors believe that mAb therapy can be a targeted therapeutic approach for the treatment of OA. Future clinical trials are required to evaluate the therapeutic efficacy of these agents by the appropriate selection of specific phenotype for targeted therapy based on the mechanism of drug action.     

Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance

Introduction: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms.

Areas covered: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation.

Expert opinion: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.     

Recent developments in colorectal cancer treatment by monoclonal antibodies

A growing understanding of the molecular mechanisms involved in cancer biology and continuous refinement of available technologies for drug discovery have prompted the development of new therapeutic tools targeting specific cancer-associated molecular pathways. Among these so-called biological therapies, monoclonal antibodies have now reached the time of clinical application. Besides initial development of the murine antibody edrecolomab, the impact of monoclonal antibodies on cancer therapy has recently been clearly demonstrated in colorectal cancer by targeting two major pathways critical to tumourigenesis: the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signalling pathways. These antibodies showed significant clinical activity in advanced colorectal cancer, especially when combined with chemotherapy. This paper reviews the status of the monoclonal chimeric antibody cetuximab (Erbitux^®) and other anti-EGFR antibodies, and of bevacizumab (Avastin^®; an anti-VEGF humanised monoclonal antibody), in colorectal cancer treatment.     

CD38 as an immunotherapeutic target in multiple myeloma

ABSTRACT

Introduction: Multiple myeloma (MM) is a currently incurable hematologic tumor with heterogeneous clinical behavior and prognosis. During the last years, survival improved due to a better understanding of MM biology and the development of novel drugs, although it still remains unsatisfactory in many cases: new drugs and treatment strategies are needed. CD38 is uniformly expressed at high levels on MM cells and, to a lesser extent, on the surface of normal hematopoietic and non-hematopoietic cells, making this molecule an interesting target for immunotherapeutic approaches.

Areas covered: This review discusses the preclinical and clinical experience on different immunotherapeutic agents targeting CD38 in MM.

Expert commentary: Monoclonal antibodies (mAbs) targeting CD38 are currently changing the treatment scenario in MM, allowing physicians to reach unprecedented results, especially when anti-CD38 mAbs are used in combination with consolidated MM treatments. Other immunotherapies targeting CD38 – such as conjugated anti-CD38 mAbs, bispecific antibodies stimulating T cells to eliminate CD38+ MM cells, and CD38-specific chimeric antigen receptor T cells – are interesting strategies, currently at earlier developmental stages.     

Genetically engineered antibodies for direct antineoplastic treatment and systematic delivery of various therapeutic agents to cancer cells

Classical antineoplastic therapeutic modalities such as surgery, radiation, and chemotherapy not only fail to cure the great majority of neoplasms, but their employment often leads to severe and debilitating side effects associated with severe neoplasm-related morbidity. Immunotherapy as a fourth modality of anti-cancer therapy has already been proven to be quite effective. The astonishing immunophenotypic (IP) heterogeneity of neoplastic cells, the different cytotoxic activity associated with the moiety linked to given monoclonal antibodies (mAb), and mostly the impressive genetic modulation capabilities of cancer cells still remain as yet unsolved difficulties in the present immunotherapy of human neoplasms. The advances in mAb production have revitalised the initial concept of use of cancer cell specific "magic bullets." Antibodies represent new approaches to anti-cancer therapy: they are neoplastic cell-specific and lethal to neoplastically transformed cells via immune effector mechanisms with no toxicity to normal tissues. They are being observed and developed, adhering to the old prayer: "Destroy the diseased tissues, preserve the normal." Strategies for the employment of antibodies include: 1) immune reaction directed destruction of neoplastic cells; 2) interference with the growth and differentiation of malignant cells; 3) antigen epitope directed transport of anti-cancer agents to neoplastic cells; 4) anti-idiotype tumour vaccines; and 5) development of engineered (humanized) mouse mAbs for anticancer therapy. In addition, a variety of agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human mAbs for selective delivery to neoplastic cells.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

Panitumumab in colon cancer: a review and summary of ongoing trials

Panitumumab is a fully human antibody developed against the human epidermal growth factor receptor receptor (EGFR/HER-1), which is overexpressed in ≥ 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and has the promise of decreased infusion reactions. Clinical studies have demonstrated that panitumumab has significant activity as a single agent and improves progression-free survival when compared with best supportive care. It can also be safely combined with standard cytotoxic chemotherapy. Ongoing studies are being performed to determine if the addition of panitumumab to first-line standard treatment for metastatic colorectal cancer will improve the progression-free and overall survival of these patients.     

VEGF antagonists

The majority of cancers have an absolute requirement for angiogenesis, the process by which new blood vessels are formed. The most potent angiogenic cytokine is vascular endothelial growth factor (VEGF) and there has been substantial research into the development of VEGF/VEGF receptor (VEGFR) antagonists. To date these strategies have included gene therapy techniques that deliver antisense oligonucleotides, soluble VEGFRs that function in a dominant negative fashion and ribozymes. Additional strategies have included the development of receptor tyrosine kinase (RTK) inhibitors and monoclonal antibodies (mAbs) directed against VEGF or the signalling receptor. The most promising agents appear to be the monoclonal anti-VEGF antibodies and the RTK inhibitors as these have demonstrated broad spectrum antitumour activity in vivo and single agent activity in early phase clinical trials in patients with advanced pre-treated breast and colorectal carcinoma and Kaposi’s sarcoma. The RTK inhibitors are of particular interest as they can be administered by mouth. Collation of the early clinical trial data suggests that VEGF antagonists are largely well-tolerated but may be associated with vascular toxicities such as haemorrhage and thromboembolic events. Combination studies of chemotherapy and VEGF antagonists are underway but the benefit of these regimens will need to be established in adequately powered Phase III studies. Potentially these agents may play a role in the treatment of both early (adjuvant) and advanced cancer. The efficacy of the drugs will be explored in a number of non-malignant conditions including rheumatoid arthritis (RA), psoriasis, diabetic retinopathy and possibly as non-steroidal contraceptives but the overall clinical development of these agents can only be optimised if appropriate biological end points are identified and incorporated into clinical trials.     

单克隆抗体免疫治疗多发性骨髓瘤

背景：多发性骨髓瘤引发的骨骼和其他组织器官的浸润破坏及全身紊乱严重影响人们生活质量.目的：旨在探究多发性骨髓瘤单克隆抗体治疗的研究新进展,以促进其临床应用.方法：由第一作者应用计算机检索 PubMed、中国期刊全文数据库（CNKI）、维普数据库和万方数据库1997年1月至2012年8月的相关文献.在标题、摘要、关键词中以“multiple myeloma, immunotherapy, monoclonal antibody,immunomodulatory drugs,bone marrow micro-environment,target,drugs, growth factor,bone metabolism, immunological response”或“多发性骨髓瘤,免疫疗法,单克隆抗体,免疫调节剂,骨髓微环境,靶目标,药物,生长因子,骨代谢,免疫反应”为检索词进行检索.选择文章内容与多发性骨髓瘤有关者,同一领域则选择近期发表在权威杂志文章.最终入选52篇文献进行综述.结果与结论：单克隆抗体免疫疗法不同于传统多发性骨髓瘤治疗,毒副反应轻,适应人群广,有重要的临床应用价值.目前相关研究主要涉及骨髓瘤细胞黏附蛋白相关单克隆抗体如CS1、多配体蛋白聚糖1、CD56单抗等,中和生长因子或抑制促生长受体相关单抗如白细胞介素6、胰岛素样生长因子1受体、血管内皮生长因子等,激活死亡受体相关单抗,提高抗肿瘤免疫反应相关单抗以及骨疾病调节因子相关单抗等,通过调节与多发性骨髓瘤发生发展有关的骨髓微环境,促进骨髓瘤细胞的凋亡,提高机体肿瘤免疫反应等机制达到较优治疗效果,但其临床应用同样存在一些局限性.