抗肿瘤单克隆抗体的临床应用

世界卫生组织预计,癌症将取代心血管病成为世界死亡人数最多的疾病。抗肿瘤药物的研发已成为制药领域的热点。单克隆抗体（单抗）能通过与肿瘤细胞上的特定靶标结合来杀死肿瘤细胞。迄今为止,已有14种抗肿瘤单抗获准上市。根据单抗的作用靶点不同,可将单抗分为抗表皮生长因子受体单抗、抗人表皮生长因子受体2单抗、抗血管内皮细胞生长因子抗体、抗白细胞分化抗原单抗。此文就以上几类抗肿瘤单抗的作用机制及临床应用进行综述。     

The use of antibodies to coagulation factors for anticoagulant therapy

Current treatments for preventing thrombotic diseases are associated with a significant risk of bleeding. Improved anticoagulant agents are therefore still required. The specificity and pharmacokinetics properties of monoclonal antibodies to coagulation factors allow novel anticoagulation approaches. Treatment with human antibodies or humanized mouse monoclonal antibodies should avoid unacceptable side effects due to immune response to the drug. Such antibodies were developed against three coagulation factor: Tissue factor (TF), Factor IX (FIX) and Factor VIII (FVIII). A fully humanized antibody was successfully derived from a mouse monoclonal antibodies to TF. In vivo studies with monoclonal antibodies to TF demonstrated efficient antithrombotic activity. Anti-TF antibodies may also prove useful in cardiovascular disorders and cancer, given the role of TF in these diseases. Mouse and human monoclonal antibodies to FIX were also efficient to prevent thrombosis in animal models of venous and arterial thrombosis and in stroke. A humanized anti-FIX antibody was tested in phase I study in healthy volunteers. The pharmacokinetics of the antibody were determined by the rapid formation of stable complexes with newly synthesised FIX. Human anti-FVIII antibodies inhibiting only partially FVIII activity were recently described. Investigations in mice have established that treatment with such anti-FVIII antibodies is efficient to prevent deep vein thrombosis. Given the low concentration of FVIII in plasma and the long half-life of antibody, treatment with anti-FVIII antibody could be very convenient, allowing one administration every month. Altogether, monoclonal antibodies to coagulation factor appear as promising novel antithrombotic drugs.     

Monoclonal antibody-based targeted therapy in breast cancer: current status and future directions

The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva) and ZD1839 (Iressa), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva^?) and ZD1839 (Iressa^?), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I – II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Treatment of sepsis: past and future avenues

In recent years, the concept has emerged that the host's inflammatory response contributes substantially to the development of septic shock and organ failure. Experimental observations prompted large scale randomised clinical trials with a variety of agents such as glucocorticoids, ibuprofen, antiendotoxin monoclonal antibodies, antagonists of platelet-activating factor, of bradykinin or of interleukin-1 receptor, and monoclonal anti-tumour necrosis factor (TNF) antibodies or soluble dimeric TNF receptor fusion proteins. All these major studies of immunomodulators in sepsis have yielded disappointing results despite showing promise during preliminary clinical studies. However, these recent failures do not mean that septic shock will forever remain an insurmountable medical challenge. Many lessons have been learned from these studies. and certain mistakes in their study design will be avoided in the future. Our understanding of the pathophysiology of sepsis and septic shock is increasing markedly; potential new treatment strategies are available and could be explored to improve the outcome of patients with sepsis.     

Monoclonal antibody-based targeted therapy in breast cancer

Advances in molecular biology have identified tumor markers that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. Activated growth factor receptors induce breast cancer cells to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy with monoclonal antibody directed against growth factor receptor pathways became important targeted therapy in breast cancer and is being pursued on various fronts. The anti-HER2 antibody trastuzumab is approved in the metastatic setting and is now trying to find the place in the adjuvant setting. Phase II and III studies with antibodies directed against VEGF and EGFR are also ongoing.     

Targeting angiogenesis with antibodies for the treatment of cancer

The treatment of cancer by targeting angiogenesis and depriving growing tumors of their blood supply has been recognized as an interesting therapeutic possibility for several decades. A multitude of development programs investigating both low-molecular-weight substances and biologicals, in particular monoclonal antibodies (mAbs), have been instigated. The generation of human or human-like mAbs has led to the recent development of therapeutic antibodies that are potentially highly beneficial in the treatment of cancer. Avastin, which binds to the pro-angiogenic factor vascular endothelial growth factor, is one of the most promising of these antibodies, and has proved beneficial in the treatment of colorectal, lung and breast cancer, with a potential to be used also in other types of cancer. However, as angiogenesis is a complex process controlled by both pro-angiogenic as well as anti-angiogenic factors, several research and development programs targeting different pro-angiogenic factors, receptors and antigens that are selectively expressed on cells in newly formed blood vessels are under way. At BioInvent International AB, research is focused on angiomotin, a newly discovered receptor for the anti-angiogenic factor angiostatin, and on the pro-angiogenic factor placenta growth factor.     

Resistance to epidermal growth factor receptor-targeted therapy.

The epidermal growth factor receptor (EGFR) has been a major target of molecular anticancer therapy. Two approaches have been developed, involving monoclonal antibodies and receptor tyrosine kinase inhibitors, and both have demonstrated benefit in clinical trials. However, evidence of resistance to these drugs has been described. Cellular levels of EGFR do not always correlate with response to the EGFR tyrosine kinase inhibitors, indicating acquired resistance to these drugs. Since EGFR antagonists interfere with the activation of several intracellular pathways that control cell proliferation, survival, apoptosis, angiogenesis, invasion and metastasis, acquired resistance can occur as a result of several different molecular mechanisms: autocrine/paracrine production of ligand, receptor mutation, constitutive activation of the downstream pathway and activation of alternative pathways. We will describe here potential mechanisms that can cause resistance to EGFR-targeted drugs. Combinations of EGFR antagonists with inhibitors targeting different signaling mechanism(s) - such as insulin-like growth factor receptor and vascular endothelial growth factor receptor - that share the same downstream mediator (e.g., phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase), may circumvent or delay the development of resistance to EGFR antagonists resulting in enhanced antitumor activities.     

Novel treatment strategies in clear-cell metastatic renal cell carcinoma

Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.     

Monoclonal antibodies in clinical oncology

Monoclonal antibodies have yet considerably modified the field of clinical oncology. The growing knowledge of key cellular pathways in tumor induction and progression, targeted therapies represent an increasing proportion of new drugs entering clinical trials. Some molecules such as trastuzumab, rituximab, alemtuzumab, cetuximab are now widely used in clinical practice. These antibodies are now tested in different indications alone or in combination with standard chemotherapy. They are also developed for the treatment of inflammatory diseases (rituximab). Numerous others antibodies are currently in pre-clinical and clinical development phases for several malignancies including renal carcinoma, melanoma, lymphomas, leukaemia, breast, ovarian and colorectal cancer. An alternative approach is to conjugate the monoclonal antibody to a toxin, a cytotoxic agent, or a radioisotope. In other cases these antibodies aim to modify the tumour microenvironment through inhibition of angiogenesis or enhancing host immune response against cancer. If the molecule targeted by the antibodies is clearly identified, most often the precise mechanism of action of these immunoglobulins is not fully understood.They can have direct effects in inducing apoptosis or programmed cell death. They can block growth factor receptors, efficiently arresting proliferation of tumor cells. Indirect effects include recruiting cells that exert cytotoxicity, such as monocytes and macrophages (ADCC). Monoclonal antibodies also bind complement, leading to toxicity known as complement dependent cytotoxicity (CDC).The side effects associated with these new treatments were in part foreseeable depending on the affected cell or function. But new or surprising side effects emerged from clinical studies. We present an overview of the monoclonal antibodies used in clinical oncology or currently in development phases. We particularly focus on recent development including new indications, clinical trial results and specific side effects of monoclonal antibodies used in the treatment of cancer.     

Monoclonal antibodies targeting the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR, HER1) autocrine pathway contributes to a number of highly relevant processes in cancer development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. The crucial role that EGFR plays in human cancers has led to an extensive search for selective inhibitors of its signaling pathway. The results of a large body of preclinical studies and clinical trials thus far conducted suggest that targeting the EGFR could bring a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies, to prevent ligand binding, and small molecules inhibitors of the tyrosine kinase enzymatic activity, that inhibit autophosphorylation and downstream intracellular signaling. Several blocking monoclonal antibodies against the EGFR have been developed. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional radiotherapy and chemotherapy. However, other antibodies against EGFR have demonstrated antitumor activity in several preclinical models of human cancer and are currently under investigation in the clinical setting, such as ICR62, ABX-EGF and EMD72000. This review will focus on all the preclinical data available on monoclonal antibodies engineered against the EGF receptor.     

The therapeutic antibodies market to 2008.

The therapeutic biologics market is currently dominated by recombinant protein products. However, many of these products are mature, and growth of the biologics market will increasingly rely on the expansion of the therapeutic monoclonal antibody sector. Successive technology waves have driven the growth of the monoclonal antibody sector, which is currently dominated by chimeric antibodies. Chimeric products, led by Remicade and Rituxan, will continue to drive market share through to 2008. However, over the forecast period, humanized and fully human monoclonal antibodies, together with technologies such as Fabs and conjugated antibodies, will play an increasingly important role, driving monoclonal antibody market growth at a forecast compound annual growth rate of 20.9%, to reach $16.7 billion by 2008. In terms of therapeutic focus, the monoclonal antibody market is heavily focused on oncology and arthritis, immune and inflammatory disorders, and products within these therapeutic areas are set to continue to be the key growth drivers over the forecast period. Underlying the growth of the market is the evolution of the monoclonal antibody company business model, set to transition towards the highly successful innovator model.     

Have we made progress in pharmacogenomics? The implementation of molecular markers in colon cancer

For the last 40 years, 5-fluorouracil (5-FU) has remained the treatment of choice in both the adjuvant and advanced treatment of colorectal cancer (CRC). However, 5-FU monotherapy produces response rates of only 10-20% in the advanced setting. 5-FU has been combined with newer agents, such as oxaliplatin and irinotecan, and this has significantly increased response rates to 40-50% in the advanced setting. More recently, novel biological agents, such as the monoclonal antibodies targeting either the epidermal growth factor receptor or vascular endothelial growth factor, have shown to provide additional clinical benefit for patients with metastatic CRC. A number of predictive markers have been identified for CRC to date. However, their usefulness as individual markers of response has led to somewhat inconclusive results. Therefore, there is a need to identify panels of predictive markers of response to therapy for advanced CRC, in order to improve these disappointing response rates. The advent of high-throughput methodologies, such as microarrays, enables tumor samples to be profiled on a global scale. This technology has been utilized to develop predictive markers for a wide range of tumor types to date, and hopefully this technology can be translated into the CRC setting with the hope of predicting the response of each individual tumor to chemotherapy.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

Cetuximab, its clinical use and future perspectives

Increase in the expression of epidermal growth factor receptors (EGFRs) has been observed in many tumours. EGFR overexpression usually correlates with a more advanced stage of the disease, a poorer prognosis and a worse chemotherapy response. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been extracellular domain receptor inhibition, using monoclonal antibodies. In this review, we summarize the current status as well as what is likely to be the future use of monoclonal antibodies directed against EGFR. We have focussed on cetuximab being the most developed one. It has been mainly studied in colorectal cancer, and the major portion of this review will focus on all the research that has been carried out on this tumour. Clinical development of cetuximab is also important in head and neck cancer and in lung cancer. Interesting studies have been carried out in pancreatic, gastric, oesophageal and ovarian tumours, as well as in malignant gliomas.     

Design of Peptidomimetics for Inhibition of HER2 Receptor Dimerization by a Combination of Virtual Screening,MD Simulations,and QSAR In Silico Methods

Malfunction or overexpression of ErbB receptors (epidermal growth factor receptors) is associated with occurrence and severity of several types of cancer. Initiation of signal cascades by ErbB2 (also known as human epidermal growth factor receptor 2/neu) in breast cancer has been blocked by monoclonal antibodies such as Trastuzumab (Herceptin), which interact with the extracellular domain of human epidermal growth factor receptor 2. Due to some disadvantages of monoclonal antibodies, a new approach in blocking human epidermal growth factor receptor 2 dimerization and activation is designing peptidomimetic ligands based on human epidermal growth factor receptor 2‐Trastuzumab interaction model. Growth of human epidermal growth factor receptor 2⁺ SK‐BR3 cells could be specifically inhibited by peptidomimetic herceptin‐based peptidomimetic 5. In this study, herceptin‐based peptidomimetic 5 was used as a benchmark peptidomimetic compound to perform a ligand‐based virtual screening followed by structure‐based screening by applying the molecular docking approach. The study aimed to explore more potent peptidomimetic molecules against extracellular part of human epidermal growth factor receptor 2. Our results showed that the newly designed peptidomimetic herceptin‐based peptidomimetic n33B in comparison with herceptin‐based peptidomimetic 5 binds more tightly to the extracellular domain of human epidermal growth factor receptor 2. Mechanistic aspects of herceptin‐based peptidomimetic n33B interaction with human epidermal growth factor receptor 2 were more investigated through 20‐ns molecular dynamic simulations. Additionally, a quantitative structure–activity relationships study was performed to develop a model for identification of structural determinants in herceptin‐based peptidomimetic 5‐based peptidomimetics.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

Epidermal growth factor receptor as a target: recent developments in the search for effective new anti-cancer agents

A number of cancer chemotherapeutics targeting the epidermal growth factor receptor (EGFR) are in development. These compounds were designed to either bind to the EGFR or inhibit signal transduction after receptor activation. Classes of inhibitory compounds include small molecules and humanized monoclonal antibodies. Many of these compounds are relatively far advanced in development. Proof of principle, with evidence of anti-tumour activity and inhibition of EGFR activation/phosphorylation, has already been demonstrated in some instances. Although these new compounds offer exciting opportunities, they bring with them real challenges in terms of the selection of appropriate trial designs as well as surrogate endpoints.