323-Comparing antibody and small-molecule therapies for cancer
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323-Comparing antibody and small-molecule therapies for cancer
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Comparing antibody and
small-molecule therapies for cancer
Kohzoh Imai* and Akinori Takaoka?
Abstract | The ‘magic bullet’ concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.
The term ‘magic bullet’, coined by bacteriologist Paul Ehrlich in the late 1800s, originally described a chemi-cal with the ability to specifically target microorgan-isms. His concept (specific targeting) was expanded thereafter to include cancer treatments, and has been successfully applied to the development of innova-tive cancer-treatment strategies with different, more specific mechanisms of action than conventional chemotherapeutic agents1. Such molecular targeting techniques2 include monoclonal antibodies (mAbs), small molecules, peptide mimetics and antisense oligonucleotides. With the advances in understand-ing of aberrant signalling pathways in various types of cancer cells, many pivotal regulators of malignant behaviour in cancer cells have emerged as candidates for molecular target-based cancer therapy. Such strat-egies have improved the management of cancers3. A crucial challenge in the development of targeted agents is to choose an appropriate approach. The two main approaches discussed here are therapeutic mAbs and small-molecule inhibitors (TABLE 1).
Key signalling molecules, such as protein tyrosine kinases, have proven to be good targets for small-molecule inhibitors that compete with ATP and inhibite kinase activity4. Such inhibitors have clini-cally effective responses in chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs)5 and non-small-cell lung cancer (NSCLC)6. Another group of targets is represented by tumour-selective cell-surface proteins, which can be recognized by antibodies. The therapeutic application of mAbs has improved response rates in patients with malignant lymphomas and is currently being assessed in other tumour types7.
Many small-molecule agents and mAbs that target growth-factor receptors and their signalling pathways have been developed and subjected to clinical trials. Some mol-ecules are targeted by both types of inhibitors, including members of the ErbB family of receptor tyrosine kinases (RTKs). The ErbB family comprises four members: epider-mal growth factor receptor (EGFR, also known as ERBB1), ERBB2 (also known as HER2), ERBB3 and ERBB4 (REFS 8,9). Both gene amplification and overexpression of EGFR and ERBB2 are frequently observed in breast, lung and colorectal cancers, and the deregulated activation of intracellular mitogenic signalling by the ErbB family has been implicated in various cancers9. Therefore, these receptors have been a focus of molecular-targeting ther-apy10. To compare mAbs and small-molecule inhibitors, this Review will highlight EGFR-targeted agents that have shown clinical success.
Accumulating clinical-trial results are showing that monotherapy with a target-specific agent might need to be reassessed. Most tumours, particularly solid tumours, are multifactorial and are frequently linked to defects in more than one signalling pathway3. Therefore, a dual-targeting or multi-targeting therapy might be more rational, not only to efficiently eliminate cancer cells, but also to limit the emergence of drug resistance. Which class of targeted agent will provide the best solution to this problem? Considering the differences in specificity or selectivity between mAbs and small-molecule inhibi-tors might lead to the further improvement of targeting strategies for cancer therapy.
In this Review we will describe the development of mAbs and small-molecule inhibitors, and then compare and contrast these two strategies using EGFR-targeted agents.
*Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan.?
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo,
Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.Correspondence to K.I.
e-mail: imai@sapmed.ac.jpdoi:10.1038/nrc1913
©2006Nature Publishing Group
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Bacteriophage display
A display method for
identifying proteins or peptides that recognize and bind to a target molecule(s).
Bacteriophages that display the antibody of interest are selected by antigen binding and are propagated in
bacteria. This helps identify therapeutic antibodies with high binding affinity.
Shedding
The release of the extracellular domain of a cell-membrane protein, such as a growth-factor receptor, from the cell surface. ERBB2 is
proteolytically cleaved, possibly by a matrix
metalloproteinase activator, although this proteolysis does not seem to be mediated by a general shedding system that can be activated by protein kinase C. ERBB2 cleavage generates a membrane-associated receptor fragment with potentially increased tyrosine kinase activity.
Monoclonal antibodies for cancer therapy
The ‘magic bullet’ concept became a reality a quarter of a century after the discovery of somatic cell hybridiza-tion, a technique for generating mAbs pioneered by Milstein and Köhler in 1975 (REF. 11). Early clinical trials with murine mAbs failed owing to their short half-life, xenogenicity and limited activity12. During this interven-ing period, the application of genetic recombination for humanizing rodent mAbs7 made large-scale production feasible, and enabled mAbs to be designed with better affinities, efficient selection, decreased immunogenic-ity and optimized effector functions. Furthermore, proteomics and genomics combined with bacteriophage display enabled the rapid selection of high-affinity mAbs. Genetic engineering has made it possible to design chimeric mouse–human mAbs, among which the anti-CD20 mAb rituximab (Rituxan) has revolu-tionized lymphoma treatment13 (TABLE 1 and FIG. 1). A humanized mAb has provided new prospects for the treatment of breast cancer. Trastuzumab (Herceptin) is the first clinically approved mAb against an ErbB family member (ERBB2)14 (TABLE 1 and FIG. 1). It has excellent anti-tumour activity, particularly when combined with the cytotoxic agents doxorubicin and paclitaxel15.
Trastuzumab is approved for the treatment of patients with metastatic breast cancer who carry an increased ERBB2 copy number. Another anti-ERBB2 mAb, pertuzumab (Omnitarg), is also under evaluation in phase II trials16. Unlike trastuzumab, which affects ERBB2 shedding17, pertuzumab sterically interferes with ERBB2 homo- and heterodimerization and sub-sequent signalling events18. On the other hand, trastu-zumab cannot prevent the formation of ligand-induced ERBB2-containing heterodimers16. So, pertuzumab is effective against trastuzumab-insensitive tumours that do not have ERBB2 amplification18,19. Therefore, pertu-zumab might be effective over a broad range of cancers with either normal or increased ERBB2 levels.
In parallel with the development of trastuzumab, our group also developed CH401, a mouse–human chimeric mAb directed against ERBB220, by a unique procedure that used a mouse-mutant hybridoma with no mouse immunoglobulin (Ig) heavy chains and a human Ig expression vector. CH401 has been evaluated in a pre-clinical study, and it significantly reduced the in vivo growth of various ERBB2-expressing tumour cells21,22. Of note, CH401 has shown an apoptosis-inducing effect, presumably through the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK)21,22. Our results showed that it is significantly more effective than trastuzumab23.
These ERBB2-targeted therapeutic mAbs have used three distinct strategies for signal blockade includ-ing interference with ligand interactions and receptor downregulation (trastuzumab), inhibition of receptor dimerization (pertuzumab), and induction of apoptosis (CH401).
EGFR is also overexpressed in various cancers, includ-ing colon and breast, and mAbs directed against EGFR have also been developed24
内容需要下载文档才能查看. Cetuximab (also known as
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Table 1 | Two classes of FDA-approved targeted agents and the spectrum of targeted cancers
内容需要下载文档才能查看Yttrium90 or Iodine131. ?In combination with irinotecan or administered as a single agent. §In combination with radiation therapy or administered as a single agent. ¶
In combination with paclitaxel or administered as a single agent. #In combination with 5-fluorouracil-based chemotherapy. ** In combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or other anthracycline-based chemotherapy regimens. ??This mAb is linked to N-acetyl-γ
calicheamicin, a bacterial toxin. After internalization of the mAb, the released toxin binds to DNA and causes double-strand DNA breaks. §§In combination with gemcitabine. AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; CRC, colorectal cancer; EGFR, epidermal
growth factor receptor; FLT3, Fms-like tyrosine kinase 3; GIST, gastrointestinal stromal tumour; NSCLC, non-small-cell lung cancer; PDGFR, platelet-derived growth factor receptor; HNSCC, head and neck squamous-cell carcinoma; TK, tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.
Complement-dependent cytotoxicity
This is one of the antigen-elimination processes that is mediated by immunoglobulins (Ig). When IgM and certain IgG subclasses (IgG1 and IgG3) bind to an antigen, one of the complement factors is strongly activated. Then, a sequence of cleavage reactions of other complement factors (classical pathway of complement activation) is triggered to activate their cytotoxic function, which leads to the destruction of the target cells.
C225; Erbitux) is a chimeric IgG1-isotype mAb that binds to EGFR with high affinity and abrogates ligand-induced EGFR phosphorylation25,26. In addition, panitumumab (ABX-EGF) was developed as a fully human IgG2-isotype mAb against EGFR, and a recent randomized phase III trial has shown that panitumumab monotherapy improved the progression-free survival of patients with previously treated metastatic colorectal cancer27.
Putative mechanisms of mAb-based cancer therapy can be classified into two categories. The first is direct action, which can be further subcategorized into three modes of action. One mode of action is blocking the function of target signalling molecules or receptors. This can occur by blocking ligand binding, inhibiting cell-cycle progression or DNA repair28, inducing the regression of angiogenesis29, increasing the internaliza-tion of receptors30,31 or reducing proteolytic cleavage of receptors17. Other modes of direct action are stimulat-ing function, which induces apoptosis, and targeting function. In the case of targeting function, mAbs can be conjugated with toxins, radioisotopes, cytokines, DNA
molecules or even small-molecule agents7,32,33 to selec-tively target tumour cells (TABLE 1 and FIG. 1). The second mechanism of mAb therapy is indirect action mediated by the immune system. The elimination of tumour cells using mAbs depends on Ig-mediated mechanisms, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), to activate immune-effector cells (FIG. 2).
Small-molecule agents for cancer therapy
RTKs and non-RTKs are crucial mediators in signalling pathways of cell proliferation, differentiation, migra-tion, angiogenesis, cell-cycle regulation and others4,34,35, and many are deregulated during tumorigenesis. Small-molecule inhibitors target these kinases by direct effects on tumour cells, rather than by causing immune responses as mAbs do. Most small-molecule inhibitors of tyrosine kinases are ATP mimetics. Imatinib mesylate (Glivec), one of the first successful small-molecule inhibitors, inactivates the kinase activity of the BCR–ABL fusion protein in CML36,37 (TABLE 1). It has shown
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Fab
内容需要下载文档才能查看Fv
Fc
Type of mAbMurine
Ibritumomab tiuxetan (CD20); IgG1κ*Tositumomab-I131 (CD20); IgG2aλ*
Chimeric
Cetuximab (EGFR); IgG1κ
Rituximab (CD20); IgG1κ
Humanized
Trastuzumab (ERBB2); IgG1κ
Bevacizumab (VEGF); IgG1Alemtuzumab (CD52); IgG1κGemtuzumab ozogamicin (CD33); IgG4κ*
Human
Panitumumab (EGFR); IgG2
Figure 1 | The classification of therapeutic monoclonal antibodies (mAbs) by the different antibody types — murine, chimeric, humanized and human. Advances in genetic engineering techniques have contributed to the development of humanized therapeutic mAbs. The fundamental structure of an intact, single immunoglobulin G (IgG) molecule has a pair of light chains (orange/red) and a pair of heavy chains (yellow/pink). Light chains are composed of two separate regions (one variable region (VL) and one constant region (CL)), whereas heavy chains are composed of four regions (VH, CH1, CH2 and CH3). The complementarity-determining regions (CDRs) are found in the variable fragment (Fv) portion of the antigen-binding fragment (Fab). Chimeric mAbs such as cetuximab and rituximab are constructed with variable regions (VL and VH) derived from a murine source and constant regions derived from a human source. Humanized therapeutic mAbs are predominantly derived from a human source except for the CDRs, which are murine. There are currently four approved humanized mAbs. Both murine and human mAbs are entirely derived from mouse and human sources, respectively. Panitumumab (ABX–EGF) is a fully human anti-epidermal growth factor receptor (EGFR) mAb, but has not yet been
approved. Furthermore, several mAbs (marked with an asterisk) are armed with cytotoxins including radionucleotides or a bacterial toxin (see text for further details). There is a significant difference between the IgG subclasses in terms of their half-lives in the blood (IgG1, IgG2 and IgG4 approximately 21 days; IgG3 approximately 7 days) and in terms of their
capability to activate the classical complement pathway and to bind Fcγ-receptors (see the legend of FIG. 2). The choice of an IgG subclass is a key factor in determining the efficacy of therapeutic mAbs. Most of the approved mAbs shown here belong to the IgG1 subclass, which has a long half-life and triggers potent immune-effector functions such as complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated cytotoxicity (CDCC) and antibody-dependent cellular cytotoxicity (ADCC). On the other hand, panitumumab is an IgG2 subclass that does not show potent CDC and ADCC, but it has recently shown its efficacy in a phase III trial as a monotherapy for the treatment of metastatic colorectal cancer. VEGF, vascular endothelial growth factor.
Antibody-dependent cellular cytotoxicity
This reaction can be initiated by the Fc portion of immunoglobulins (Ig).Phagocytes such as
monocytes/macrophages, dendritic cells, natural killer cells and neutrophils take up IgG-coated target cells through binding with Fcγ-receptors on the surface of the phagocytes. This is eventually followed by the elimination of target cells.
ATP mimetics
These small-molecule inhibitors competitively bind to the ATP-binding cleft at the activation loop of target kinases, thereby inhibiting their kinase activity.
remarkable efficacy for the treatment of patients with Philadelphia chromosome-positive CML38. It is also a multi-targeted inhibitor of other tyrosine kinases, includ-ing KIT, which is key to the pathogenesis of metastatic GISTs, and the platelet-derived growth factor receptors PDGFRα and PDGFRβ, which are key to the patho-genesis of PDGF-driven tumours such as glioblastoma and dermatofibrosarcoma protuberans39.
EGFR is also a rational target for small-molecule inhibitors40. Gefitinib (Iressa)6 and erlotinib (Tarceva)41 selectively inhibit EGFR, and both are efficacious against EGFR-expressing cancers such as NSCLC and head and neck squamous-cell carcinoma (HNSCC) (TABLE 1). Phase II studies of these agents have also shown their efficacy with or without concurrent chemotherapy in HNSCC, and several phase III trials of gefitinib are ongoing42. Erlotinib in combination with an anti-metabolite, gemcitabine, is also approved for treating advanced pancreatic cancer.
Unlike mAbs, small-molecule agents can trans-locate through plasma membranes and interact with the cytoplasmic domain of cell-surface receptors and intracellular signalling molecules. Therefore, various small-molecule inhibitors have been generated to target cancer-cell proliferation and survival by inhibiting Ras prenylation43, Raf–MEK kinase44, phosphatidylinositol 3-kinase (PI3K), the mammalian target of rapamycin (mTOR) pathway or heat shock protein 90 (HSP90) (REF. 45); cancer-cell adhesion and invasion by inhibiting SRC kinase46 or matrix metalloproteinases (MMPs)47; or neovascularization by inhibiting the vascular endothelial growth factor RTK (VEGFR).
As a new type of small-molecule agent, sorafenib (Nexavar) is known to exert its inhibitory effect on not only different isoforms of Raf serine kinase but also various RTKs such as VEGFR, EGFR and PDGFR34. This dual-action kinase inihibitor shows broad-spectrum anti-tumour activity by inhibiting tumour proliferation and angiogenesis48. Another new anti-angiogenesis small-molecule drug, sunitinib malate (Sutent), is also a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT and Fms-like tyrosine kinase 3 (FLT3)48. Potential targets for the development of small-molecule agents have also been identified in the ubiquitin–proteasome
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(TABLE 1). Further The timelines 6.
Although therapeutic mAb development requires 49. Furthermore, 50 than new chemical entities (NCEs) including 51, especially in the field of oncology50. On the other hand, small-molecule agents are less expensive and more convenient to administer than mAbs.
mAbs and small-molecule inhibitors differ in sev-eral pharmacological properties. Anti-EGFR mAbs are large proteins (around 150 kDa) and are generally intravenously administered, whereas EGFR TKIs are orally available, synthetic chemicals (approximately 500 Da). The large molecular weight of mAbs is probably the cause of their inefficient delivery into brain tissues because of the blood–brain barrier, so therapeutic mAbs for brain cancer are usually deliv-ered intra-tumorally52. In addition, we speculate that owing to the difference in molecular size, intact Igs such as IgG subclasses might be less efficient for tis-sue penetration, tumour retention and blood clearance than small-molecule agents. In fact, there are marked differences between these two classes of agents in several pharmacokinetic properties. According to FDA labelling, the mAb half-lives (that is, cetuximab: 3.1–7.8 days, allowing for once-weekly dosing) are much longer than those of small-molecule agents (that is, gefitinib, approximately 48 hrs; erlotinib, approxi-mately 36 hrs; allowing for once-daily dosing). Also, pharmacokinetic studies showed that plasma concen-trations of small-molecule agents can vary at a given dose between patients53. This might be explained by the oral administration of small-molecule agents versus the intravenous administration of mAbs. Furthermore, it might also be speculated that the degradation sys-tem for small-molecule agents (chemicals) might vary more in individuals than that for mAbs (proteins).Because of their inability to pass through the cellular membrane, mAbs can only act on molecules that are expressed on the cell surface or secreted54. Bevacizumab
Figure 2 | Schematic model of antibody action by immune mechanisms.
Following the binding of monoclonal antibodies (mAbs) to a specific target on a tumour cell, C1q complement factor interacts with the CH2 constant region of the mAb, which leads to the activation of a proteolytic cascade of the complement classical pathway and consequently induces the formation of a membrane-attack complex (MAC) for the lysis of tumour cells; this effect is termed complement-dependent cytotoxicity (CDC). C3b, which is generated during this cascade reaction, functions as an opsonin to facilitate phagocytosis and cytolysis through its interaction with the C3b receptor (C3bR) on a macrophage or natural killer (NK) cell118; this activity is termed complement-dependent cell-mediated cytotoxicity (CDCC). In addition, mAb-binding to tumour cells induces antibody-dependent cellular cytotoxicity (ADCC); immune-effector cells such as macrophages and NK cells are recruited and interact with the CH3 region of the mAbs through FcγRIIIa expressed by both effector cells. Then, mAb-coated tumour cells are phagocytosed by macrophages or undergo cytolysis by NK cells. On the other hand, there is a negative regulation to modulate the cytotoxic response against tumours
through FcγRIIb, which is expressed on the cell surface of macrophages. Immunoglobulin G1 (IgG1) and IgG3 can activate the classical complement pathway and interact with Fcγ receptors more potently than IgG2 or IgG4. In particular, IgG4 cannot activate the classical complement pathway.
Chymotryptic protease in the 26S proteasome
The 26S proteasome is a multicatalytic complex, which is composed of the 20S
catalytic core subunit and the 19S regulatory subunit that recognize and degrade ubiquitylated proteins. A chymotrypsin-like proteolytic activity is one of the catalytic activities of this core subunit for the hydrolysis of peptide substrates.
pathway, which is crucial in processes including cell-cycle arrest and apoptosis. Bortezomib (Velcade), which was first developed as a selective, reversible inhibitor of the chymotryptic protease in the 26S proteasome, has been reported to be effective against various cancers, particularly haematological malignancies (TABLE 1).
Comparison between mAbs and small-moleculesMany preclinical and clinical studies have indicated that targeting EGFR could represent a significant contribu-tion to cancer therapy. Because both mAb and small-molecule EGFR inhibitors have been approved as cancer therapies, we will use them as our primary example to compare mAbs and small-molecule inhibitors. There is no clear difference in the spectrum of cancers targeted by
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