M A T C: Onoclonal Ntibody Herapy For Ancer

Annu. Rev. Med. 2003. 54:34369 doi: 10.1146/annurev.med.54.101601.152442 Copyright c 2003 by Annual Reviews.
All rights reserved
MONOCLONAL ANTIBODY THERAPY FOR CANCER

Margaret von Mehren, Gregory P. Adams, and Louis M. Weiner
Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111; e-mail: m vonmehren@fccc.edu, gp adams@fccc.edu, lm weiner@fccc.edu
Annu. Rev. Med. 2003.54:343-369. Downloaded from www.annualreviews.org by b-on: Universidade de Lisboa (UL) on 02/26/11. For personal use only.
Key Words immunoconjugate, immunotoxin, radioimmunotherapy, antibody-dependent cellular cytotoxicity I Abstract Monoclonal antibody therapy has emerged as an important therapeutic modality for cancer. Unconjugated antibodies show signicant efcacy in the treatment of breast cancer, non-Hodgkins lymphoma, and chronic lymphocytic leukemia. Promising new targets for unconjugated antibody therapy include cellular growth factor receptors, receptors or mediators of tumor-driven angiogenesis, and B cell surface antigens other than CD20. Immunoconjugates composed of antibodies conjugated to radionuclides or toxins show efcacy in non-Hodgkins lymphoma. One immunoconjugate containing an antibody and a chemotherapy agent exhibits clinically meaningful antitumor activity in acute myeloid leukemia. Numerous efforts to exploit the ability of antibodies to focus the activities of toxic payloads at tumor sites are under way and show early promise. The ability to create essentially human antibody structures has reduced the likelihood of host-protective immune responses that otherwise limit the duration of therapy. Antibody structures now can be readily manipulated to facilitate selective interaction with host immune effectors. Other structural manipulations that improve the selective targeting properties and rapid systemic clearance of immunoconjugates should lead to the design of effective new treatments, particularly for solid tumors.
INTRODUCTION
The description of techniques for the production of monoclonal antibodies (MAb) by Kohler & Milstein 25 years ago led to the development of multiple reagents employing these structures. Antibodies, which initially were viewed as targeting missiles, have proved much more complex in their targeting and biologic properties than the elds pioneers envisioned them. The ability to manipulate the genes of antibodies with microbiologic techniques has allowed signicant modications of these structures. Murine proteins can be readily transformed into human or humanized formats that are not readily recognized as foreign by the
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human immune system. In addition, novel antibody-based structures with multiple antigen recognition sites, altered size, or effector domains have been shown to inuence the targeting ability of antibodies. Coupled with the identication of appropriate cancer targets, antibody-based therapeutics are nding increasing applications in cancer treatment, and they can be effective alone, in conjunction with chemotherapy or radiation therapy, or when conjugated to toxic moieties such as toxins, chemotherapy agents, or radionuclides. This review focuses on antibody-based agents with signicant efcacy and novel approaches with clinical promise.
IMMUNOGLOBULIN STRUCTURE IgG

IgG molecules are the most common antibodies employed in cancer therapy. They are comprised of two identical light chains and two identical heavy chains, each composed of variable domains and constant domains (Figure 1). The variable region contains the hypervariable or complementarity-determining regions (CDRs). These short, highly variable amino acid sequences are the major site of interaction with antigen. There are three CDRs (CDR1, CDR2, and CDR3) on each variable chain. Both the light chains and the heavy chains are held together by disulde bonds and noncovalent interactions between several of the domains. The complex is oriented with bilateral symmetry: light chainheavy chainheavy chainlight chain. The IgG molecule is divided into three functional domains, two antigenbinding (Fab) domains with identical antigen specicity connected by a highly exible hinge domain to the Fc (effector) domain that interacts with complement,
Figure 1 Schematic diagram depicting the structures of an IgG molecule and a variety of engineered antibody molecules derived from various IgG domains.
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immune effector cells, and receptors involved in maintaining constant concentrations of IgG in the circulation.
Antibody Fragments
For many years, IgG molecules have been enzymatically digested into smaller functional fragments [Fab and F(ab )2]. More recently, the genes encoding the variable and constant domains have been used to construct a variety of recombinant antibody-based fragments. These range in size from peptides comprised of an individual CDR (1) to multidomained molecules with four antigen binding sites (2). The smallest antibody-based fragments, individual CDRs and single-variable domains, often exhibit lower afnity and less antigen specicity than corresponding intact antibody molecules (1, 3). Single-chain Fv (scFv) molecules, composed of peptide-linked VH and VL domains, are rapidly emerging as key players in the engineered antibody eld. With a size of 25 kDa, these molecules are both effective targeting vehicles in their own right and versatile components for the construction of larger antibody-based regents. ScFv molecules can be produced from genes isolated from hybridomas expressing MAb of a desired specicity (4) or can be isolated by panning (selection) from a combinatorial phage display library (5). The small size of scFv molecules mediates their rapid renal elimination, leading to highly specic tumor localization. Because of this property, radiolabeled scFv molecules are highly attractive agents for use in tumor detection (6). ScFv can be dimerized to yield larger molecules that exhibit a slower systemic clearance and a greater avidity for cells that overexpress their target antigen, making them potentially useful in tumor therapy. Various strategies can be employed to dimerize scFv molecules. These include the creation of disulde-linked (scFv)2 (7) or gene-fused (scFv)2, with a peptide spacer joining two scFv, and the shortening of the linker between the light and heavy chain, forcing the production of diabodies by noncovalent associations between two molecules (8). Larger divalent molecules, termed minibodies, can be produced by fusing the gene for an scFv to that for a CH3 domain (9). An additional advantage of the minibody format is the greater stability of the complex conferred by the afnity between the CH3 domains. Tandem diabodies, with four antigen-binding sites, can be produced by joining two diabody components with peptide spacer (2). The ideal antibody-based molecule depends on the application. If a naked antibody can directly mediate an antitumor effect, the greatest possible bioavailability is desired. This is best achieved by leaving the antibody in the native IgG format, which will exhibit a prolonged residence in the circulation. However, the native IgG format could lead to unacceptable bone marrow toxicity if the antibody is conjugated to a therapeutic radioisotope for radioimmunotherapy (RAIT) applications. For RAIT, smaller, more rapidly cleared molecules such as minibodies or diabodies can reduce nontargeted marrow toxicity. Furthermore, because physiologic barriers such as heterogeneous blood supply and elevated interstitial pressure
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(10) impede the penetration of antibodies into tumors, these smaller molecules may have other advantages over intact IgG. Jain & Baxter (11) determined that an intact IgG molecule would take 54 h to move 1 mm into a solid tumor, whereas a Fab fragment would travel the same distance in only 16 h.
DESIRABLE CHARACTERISTICS OF ANTIBODY TARGETS

A variety of protein and carbohydrate molecules on the surface of cancer cells are potential targets for antibody-directed therapies. Clinically useful targets may be uniquely expressed by cancer cells or expressed at higher levels by cancer cells than by normal cells. As a result, antibodies will selectively bind to cancer cells. Receptors on the surface of cancer cells are particularly attractive targets for therapeutic antibodies if binding of the receptor perturbs a downstream signaling event, or inhibits the binding of a natural ligand to its receptor and therefore interferes with a normal signaling pathway. If an antibody is linked to a radioactive particle, immunotoxin, or chemotherapeutic agent, it may be benecial to target a receptor that internalizes upon antibody binding, leading to internalization of the toxic agent.
MECHANISMS OF ACTION FOR ANTIBODIES AS THERAPEUTIC AGENTS

Antibodies may exert antitumor effects by inducing apoptosis (12), interfering with ligand-receptor interactions (13), or preventing the expression of proteins that are critical to the neoplastic phenotype. In addition, antibodies have been developed that target components of the tumor microenvironment, perturbing vital structures such as the formation of tumor-associated vasculature. Some antibodies target receptors whose ligands are growth factors, such as the epidermal growth factor receptor. The antibody thus inhibits natural ligands that stimulate cell growth from binding to targeted tumor cells. Alternatively, antibodies may induce an anti-idiotype network (14), complement-mediated cytotoxicity (15), or antibodydependent cellular cytotoxicity (ADCC) (16). An anti-idiotypic network results from the recognition of the antibody, called Ab1, by the host immune system. The antigenic binding site within the variable regions of the antibody is seen as foreign. When an antibody, termed Ab2, is formed against this binding site, it recapitulates the three-dimensional structure of the antigen targeted by Ab1. This chain of events can keep occurring, thus perpetuating the immune response against the primary antigen (17, 18). Some classes of immunoglobulins can activate complement or natural killer (NK) cells. The rst component of the complement cascade, C1, is capable of binding the Fc portion of IgM and IgG molecules. C1 activation triggers the classical complement cascade, leading to the recruitment of phagocytic cells and death of the antibody-bound cell. This process occurs more efciently with IgM molecules, but it can also occur if IgG molecules are clustered on the cell surface. Cells coated by IgG1 or IgG3 isotype antibodies can also activate effector cells
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via the binding of the terminal Fc portion of the antibody to Fc receptors, found on NK cells, neutrophils, mononuclear phagocytes, some T cells, and eosinophils. ADCC occurs with the release of cytoplasmic granules containing perforins and granzymes from these effector cells. This phenomenon can be amplied by constructing bispecic antibodies that contain two binding domains, one that targets a tumor antigen and one that targets the immunoglobulin Fc receptor on immune effector cells, thereby activating the effector cells for tumor lysis.
ANTIBODY LIMITATIONS
Initial clinical trials with MAb produced some striking antitumor effects (19), but most of the early experiences illustrated the obstacles to successful therapy (Table 1). Most of the MAb employed in early clinical trials were derived from mice, and patients exposed to them developed human antimouse antibody (HAMA) responses, which limited the number of treatments patients could safely receive (20). Molecular engineering techniques have overcome this obstacle by grafting critical sequences in the human heavy-chain backbone onto the xenogeneic murine antibody structure, paring the interspecies differences and reducing the immunogenicity of the resulting antibodies. Numerous techniques have further reduced immunogenicity, and it is now possible to create fully human immunoglobulins with limited capacity to induce HAMA. However, these approaches do not inhibit the production of anti-idiotype antibodies (see previous section). Some tumor antigens are shed or secreted. Antibodies that target these antigens will bind their targets in the circulation, limiting the amount of unbound antibody available to bind to tumor (21). Barriers that impede antibody distribution within tumors include (a) disordered tumor vasculature, (b) increased hydrostatic pressure within tumors and (c) heterogeneity of antigen distribution within tumors (11). It has been estimated that, due to these barriers, an IgG molecule will take 2 days to travel 1 mm and 78 months to travel 1 cm within a tumor. Estimates for a smaller antibody-based molecule, such as a Fab fragment, are 1 day to travel 1 mm and 2 months to travel 1 cm. If antibodies do reach their targets, there is little evidence
TABLE 1 Obstacles to effective antibody therapy 1. Immunogenicity of xenogeneic antibodies 2. Shedding of antigen into circulation 3. Disordered vasculature in tumors 4. Increased hydrostatic pressure in tumors 5. Heterogeneity of antigen on tumor surface 6. Limited numbers of effector cells at tumor 7. Immunosuppressive tumor microenvironment
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that they efciently mediate ADCC in vivo. For this to occur, sufcient numbers of effector cells, such as macrophages, NK cells, or cytotoxic T cells, must be present in the tumor (22). Finally, many tumors are known to secrete compounds that downregulate the immune response (23, 24), or to have decreased effector cells as a consequence of hypoxia (25). Despite these impediments, preclinical and clinical data with improved antibody-based molecules continue to demonstrate a role for antibody-based therapy as a component of the oncologic armamentarium.
ANTIBODY THERAPEUTICS
The ability to identify therapeutic targets and produce antibodies with limited immunogenicity has led to the production and testing of a host of agents, several of which have demonstrated clinically important antitumor activity and have received FDA approval for treatment of cancer. We focus here on antibodies with proven efcacy, classied according to the tumor or antigen system that is targeted.
Hematologic Malignancy Antigens

B CELL ANTIGENS Initial studies employing antibodies directed against B cell determinants showed that the passive administration of these antibodies led to clearance of circulating tumor cells and rare objective clinical responses (26). In a series of landmark studies, Levy and colleagues prepared customized antibodies reactive with a given lymphoma patients idiotype that was uniquely expressed on the surface of the malignant B cell clone. Each patients idiotype served as a tumor-specic signature that could be targeted by a customized MAb. The procedures for preparing such antibodies for each patient were laborious, but 50% of treated patients experienced signicant clinical responses, with some patients achieving durable complete remissions (19). The addition of chemotherapy agents, interferon, or other cytokines did not appreciably improve treatment outcomes. Effective therapy had to overcome circulating lymphoma idiotype proteins that diverted antibodies from their cellular targets, and resistance to therapy resulted in part from the emergence of idiotype-negative variants. The mechanisms underlying responses to these antibodies have not been completely elucidated but may include mechanisms such as ADCC (see below) and perturbation of signal transduction through idiotype engagement (27). Due to the immunosuppression of lymphoma patients, relatively few patients developed HAMA that interfered with repeated therapeutic antibody administration. This exciting approach was very cumbersome, as it required the generation of patient-customized reagents. These results could not be replicated using antibodies that recognize shared idiotypes expressed by a large proportion of lymphoma patients (28). Despite this set of impediments, these important observations have informed much of the subsequent work in this eld. CD52
The CAMPATH-1 antibody has specicity for CD52, a glycopeptide that is highly expressed on T and B lymphocytes. It has been tested as a therapeutic
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agent for chronic lymphocytic and promyelocytic leukemias, as well as other non-Hodgkins lymphomas, and as a means to deplete T cells from allogeneic transplant grafts. Half of the patients with udarabine-resistant chronic lymphocytic leukemia or B-prolymphocytic leukemia exhibited clinical responses to CAMPATH-1 (29). A larger phase II study reported a 42% response rate in patients with relapsed or refractory chronic lymphocytic leukemia, but at the cost of an increase in opportunistic infections and septicemia. CAMPATH-1 has also been evaluated as rst-line therapy for patients with chronic lymphocytic leukemia. All patients responded with loss of peripheral blood malignant lymphocytes. However, patients with involvement of lymph nodes and/or spleen were less likely to respond completely. There was evidence of reactivation of cytomegalovirus infections. Subcutaneous administration of the antibody was found to be safe and effective. A humanized version of the antibody (CAMPATH-1H) has been extensively tested. In a phase II multicenter study of CAMPATH-1H in previously treated patients with low-grade non-Hodgkins lymphomas, 50 patients with relapsed or refractory disease were treated with 30 mg of CAMPATH-1H 3 times weekly for up to 12 weeks (30). Infection, anemia, and thrombocytopenia were common, and myocardial infarction occurred in one patient with a prior history of angina and congestive heart failure. The overall response rate was 20% (16% partial response, 4% complete reponse). Responses were short in duration, with a median time to progression of 4 months. Patients with mycosis fungoides responded more frequently and had a longer time to progression (10 months) than did patients with low-grade non-Hodgkins lymphoma (4 months). Treatment was associated with reactivation of herpes simplex, oral candidiasis, pneumocystis carinii pneumonia, cytomegalovirus pneumonitis, pulmonary aspergillosis, disseminated tuberculosis, and seven cases of pneumonia and septicemia. CAMPATH-1 has been used to deplete T cells from allogeneic transplant grafts in patients with hematologic malignancies (31, 32). The initial study suggested that the addition of CAMPATH-1 signicantly decreased graft rejection and graftversus-host disease compared with conventional therapy. However, the frequency of graft rejection and graft failure was higher. A retrospective review of patients with acute lymphocytic or acute myelogenous leukemia who underwent allogeneic transplantation with CAMPATH-1purged marrow suggested no impact on the graft-versus-leukemia effect, as there was no increase in leukemia relapse (33). Additionally, the incidence of Epstein-Barr virus (EBV)related lymphoproliferative disorders was decreased in allogeneic transplant patients who had T cell depletion with CAMPATH-1 therapy compared with other methods of T cell depletion (e.g., E-rosettes or other MAb) (34). CAMPATH-1 eliminated B cells within the graft, thus eliminating a potential reservoir of EBV or targets for subsequent infection.
CD20
The testing and evaluation of the chimeric anti-CD20 antibody, IDECC2B8, also known as rituximab, demonstrated impressive clinical responses. Rituximab is the rst MAb to be approved by the FDA for use in human malignancy
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(35, 36). Rituximab is humanized and multiple doses can be safely administered. In vitro studies have demonstrated multiple mechanisms by which anti-CD20 antibodies lead to cell death: ADCC, complement-mediated lysis, and apoptosis that is diminished by inhibitors of Lck and Fyn tyrosine kinases, calcium chelators, and caspase inhibitors (37). In the phase I study to determine the maximum tolerated dose, patients with relapsed low-grade and intermediate/high-grade non-Hodgkins lymphoma received four weekly infusions of rituximab (37). Thrombocytopenia and B cell lymphocytopenia were observed. The lymphocytopenia persisted for 36 months. Six of 18 patients, all of whom had low-grade lymphomas, demonstrated partial responses (33%). Phase II studies using the maximum tolerated dose, 375 mg/m2, conrmed the efcacy of this therapy, demonstrating 46% and 48% response rates in two separate studies (38, 39). Although the numbers of circulating B cells were reduced by therapy, there were no documented changes in serum immunoglobulin levels. Bacterial and viral infections were seen in patients with relapsed indolent lymphomas, but in contrast to the CAMPATH-1 experience, treatment with rituximab did not result in signicant morbidity due to infections. Patients with small-lymphocytic-B-cell lymphoma had lower response rates, probably related to the lesser expression of CD20 on these tumor cells. Although phase I testing had not suggested signicant activity in intermediate/ high-grade lymphomas, a phase II trial evaluated rituximab in relapsing or refractory diffuse large B cell lymphoma, mantle cell lymphoma, or other intermediateor high-grade B cell non-Hodgkins lymphomas (40). The study randomized 54 patients to either 8 weekly treatments of 375 mg/m2 intravenous rituximab or 375 mg/m2 in week one followed by 7 weekly intravenous infusions of 500 mg/m2. Five complete responses and 12 partial responses were observed, for an overall response rate of 31%; there was no evidence of superiority of either treatment regimen. Patients with refractory disease and those with histologies other than diffuse large B cell lymphoma appeared to have lower response rates. A novel use of rituximab has been reported for cutaneous B cell lymphoma; patients who received intralesional injections of the antibody showed partial clearing of nodules (41). Rituximab has been tested in conjunction with chemotherapy (42). Preclinical data show that this antibody can sensitize chemotherapy-resistant cell lines to the cytotoxic effects of chemotherapy (43). Forty patients with low-grade or follicular B cell non-Hodgkins lymphoma were enrolled in the study. Thirty-ve patients received all six planned cycles of CHOP every 21 days, with six infusions of rituximab at a dose of 375 mg/m2 given before, during, and after chemotherapy. Three patients did not complete treatment due to intercurrent infections (n = 2) and patient choice (n = 1), and two patients were withdrawn from the study prior to therapy. The overall response rate was 95% (38/40), with 55% complete responses and 40% partial responses. Fewer complete responses were noted in patients with bulky disease. Median response duration and time to progression had not been reached after 29+ months of follow-up. Seven of 8 patients who had initially been positive for the bcl-2 translocation became negative for the translocation
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by PCR assay after therapy; this has not been seen with CHOP chemotherapy alone (44). A preliminary analysis of a randomized study in elderly patients with diffuse large-cell lymphoma comparing standard CHOP chemotherapy to CHOP with rituximab demonstrated a 76% complete response rate in the combination arm compared with 60% complete response rate in the chemotherapy arm without signicant differences in toxicity between the two groups (40). Furthermore, the addition of rituximab prolonged event-free survival and overall survival. Rituximab also has been evaluated in conjunction with udarabine in low-grade lymphomas. Signicant leukopenias were associated with this combination, requiring a dose reduction in the udarabine. An interim analysis after accruing 30 of the 40 planned patients revealed a response rate of 93% with median response duration of over 14 months. Cytogenetic responses were also observed in some patients (45). The signicance of such responses is unclear. In a study of rituximab with CHOP chemotherapy in patients with mantle cell lymphoma, loss of a cytogenetic marker was not associated with improved progression-free survival (46). Another setting in which rituximab has been tested is following high-dose chemotherapy with autologous transplantation (47). Patients with at least a 75% reduction in tumor volume following CHOP chemotherapy underwent high-dose chemotherapy with stem cell transplantation. Two and six months following transplant, patients received four weekly treatments with rituximab. A preliminary report of this study describes four patients who have received one post-transplant cycle and eight who have received two post-transplant cycles. Two patients are reported with a partial response and another two patients with unconrmed complete response. Circulating CD20-positive cells, including lymphoma cells, may affect the efcacy of rituximab. Peak levels of circulating antibody inversely correlate with pretreatment B cell counts as well as the bulk of tumor (38, 39). Greater numbers of peripheral lymphocytes and/or tumor bulk serve as an antigen sink, removing antibody from the circulation. For patients with bulky disease, a higher antibody dose or a greater number of cycles may be warranted, since patients with lower serum rituximab concentrations have had statistically signicant lower response rates. A dosage of eight cycles of weekly rituximab has been used safely in lowgrade and follicular non-Hodgkins lymphoma (48). The efcacy of rituximab in chronic lymphocytic leukemia is clearly affected by lower circulative levels of the antibody. Initial studies revealed a 20% response rate. Chronic lymphocytic leukemia has lower antigen density than many lymphomas that express CD20, and the cells circulate, acting as an antigen sink. A dose-escalation study demonstrated a clear dose-response relationship (49). Rituximab therapy rarely selects for the emergence of an antigen-negative population of tumor cells. At the present time, little is known about mechanisms of resistance (49a). This phenomenon has been documented in a patient with a follicular mixed small- and large-cell lymphoma, who was treated with rituximab after multiple chemotherapy regimens (50). Approaches to overcome antigen-negative populations include combining rituximab with chemotherapy or with antibodies
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targeting other antigens expressed by the lymphoma or leukemia being treated. For example, chronic lymphocytic leukemia expresses both CD20 and CD52. Studies are evaluating combination therapy with both rituxan and CAMPATH-1H (51). Other antigens that could target B cell lymphomas and leukemias include CD22, which is expressed on pro-B and pre-B cell lymphomas, and the major histocompatability class II antigen, HLA-DR, found on B lymphocytes as well as macrophages and dendritic cells. Epratuzumab, which targets CD22, and apolizumab, which targets a subset of HLA-DR molecules, are currently undergoing testing (52). Clearly these agents are candidates for combination therapy with rituximab. In some patients with circulating blood tumor cells, rituximab therapy has induced an infusion-related syndrome characterized by fever, rigors, thrombocytopenia, tumor lysis, bronchospasm, and hypoxemia, requiring discontinuation of the antibody infusion. Symptoms typically resolve with supportive care and patients may continue further therapy without sequelae (53). Another case report documents rapid tumor lysis in a patient with B cell chronic lymphocytic leukemia with a pretreatment lymphocytosis of >100 109/liter (54). Occasional severe mucocutaneous reactions have been reported, some of which have been fatal. These present as paraneoplastic pemphigus, Stevens-Johnson syndrome, and toxic epidermal necrolysis (55).
Solid Tumor Antigens

HER-2/neu (c-erbB-2), a member of the epidermal growth factor receptor (EGFR) family, has been targeted for antibody therapy because it is overexpressed on 25% of breast cancers, as well as other adenocarcinomas of the ovary, prostate, lung, and gastrointestinal tract. Trastuzumab (56, 57), also known as Herceptin and rhuMAb HER2, is a humanized antibody derived from 4D5, a murineMAb, which recognizes an epitope on the extracellular domain of HER2/neu. A phase II trial in women with metastatic breast cancer reported an objective response rate of 11.6%, with responses seen in the liver, mediastinum, lymph nodes, and chest wall. Patients received ten or more treatments with the antibody, and none developed an antibody response against trastuzumab. In a second phase II study, 222 women with metastatic breast cancer were treated with 2 mg/kg of trastuzumab weekly, with an objective response rate of 16% (56). The median response duration was 9.1 months, with a median overall survival of 13 months, both of which are superior to outcomes reported for second-line chemotherapy in metastatic disease. In each of these trials, about 30% of the patients had stable disease, lasting more than 5 months. Overexpression of HER-2/neu that is associated with gene amplication correlates with a clinical response to trastuzumab. Earlier studies utilized variable criteria to dene HER2 positivity that may account for the differences in the response rates. The standard assay for determining HER2 expression is the Hercept test. Breast tumors with 3+ expression by this assay correlate with gene overexpression; those with 2+ expression require testing by
HER-2/NEU
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uorescence in situ hybridization to conrm gene amplication. Intriguingly, preclinical studies have demonstrated decreased expression of vascular endothelial cell growth factor (VEGF) and vascular permeability factor with 4D5 therapy, suggesting that an antiangiogenesis mechanism may account for some of the clinical impact of this antibody (58). Trastuzumab continues to be evaluated clinically in diverse adenocarcinoma types. A large, randomized phase III trial evaluating cytotoxic chemotherapy alone and with trastuzumab has shown the efcacy of combination therapy (59). Patients receiving initial therapy for metastatic breast cancer were treated with cyclophosphamide plus doxorubicin or epirubicin, or with paclitaxel if they had received an anthracycline in the adjuvant setting. Patients were randomized to receive this chemotherapy alone or in combination with weekly antibody therapy. Response rates for combination therapy with an anthracycline regimen increased from 43% to 52% with the addition of trastuzumab. Using a taxane regimen, response rates increased from 16% to 42% with the addition of trastuzumab. In addition, there was evidence that the addition of trastuzumab to chemotherapy improved survival at one year by 16% (60) and improved survival at 29 months by 25% (61). Myocardial dysfunction was observed more frequently in patients receiving doxorubicin or epirubicin when trastuzumab was added. Therefore, trastuzumab is not recommended in combination with anthracyclines. Based on these clinical trial results, trastuzumab was approved by the FDA to treat women with metastatic breast cancer with HER-2/neu overexpression, given either alone or in combination with paclitaxel. Herceptin also has activity in combination with vinorelbine (62), docetaxel, cisplatin (63), and the combination of gemcitabine and paclitaxel (64). In addition, breast cancer patients with lymph node involvement whose cancers overexpress HER-2/neu are candidates for participation in a randomized phase III trial evaluating standard adjuvant chemotherapy with or without trastuzumab. The use of Herceptin for breast cancer has been a therapeutic success. Although other adenocarcinomas may overexpress HER-2/neu, clinical trials have not documented consistent therapeutic successes in other cancers. The Gynecologic Oncology Group evaluated Herceptin in patients with recurrent or refractory ovarian or primary peritoneal carcinoma (65). An overall response rate of 7.3% was found with a median treatment of 8 weeks and median progression-free interval of 2 months. HER-2/neu has also been found on prostate cancer and nonsmall-cell lung cancer.
Epidermal Growth Factor Receptor

EGFR is overexpressed on many cancers. The receptor and its ligands, epidermal growth factor (EGF) and transforming growth factoralpha (TGF ), act in an autocrine loop to stimulate the growth of breast cancer cells. In vitro, some anti-EGFR antibodies have been shown to inhibit the binding of the receptor ligands (66, 67). Antibodies that block the binding of EGFR ligands limit receptor activation by
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tyrosine kinases and inhibit growth of normal broblasts (68) as well as tumor cells in culture (69). Also, combining anti-EGFR antibodies with cisplatin signicantly decreases the IC50 of cisplatin (70), and cures of established tumors have occurred when anti-EGFR antibodies are combined with cisplatin (71) or doxorubicin (72). Sequential treatment with topotecan followed by C225 (a chimerized version of the anti-EGFR antibody MAb225) in vitro leads to supra-additive growth inhibition in breast, ovary, and colon cancer cell lines (73). C225 delivered simultaneously with radiation reduces phosphorylation of the EGFR and STAT-3, enhancing apoptosis (74). In vitro and in vivo studies suggest that anti-EGFR antibodies may lead to terminal differentiation of squamous cell carcinoma cells, with accumulation of cells in G0G1 phases of the cell cycle and expression of cell surface markers such as involucrin and cytokeratin-10 (75). MAb225 blocks in vitro phosphorylation of the EGFR and induces receptor internalization, as occurs with binding of the natural ligand (76). However, receptor processing is slower with antibody engagement than with natural ligand engagement (77). Smaller bivalent F(ab )2 and univalent Fab forms of this antibody also inhibit growth and decrease receptor phosphorylation, although the bivalent form is superior to the monovalent form (78). Since the smaller fragments lead to tumor regressions, the efcacy of antibody therapy is not dependent on ADCC, as these smaller fragments lack the Fc portion of the antibody required for ADCC. Rather, the efcacy of MAb225 is due to its ability to inhibit binding of the natural ligand, limit receptor phosphorylation and thus downstream signals, and induce receptor internalization. The chimeric form of MAb225, C225, has been evaluated in vitro and in vivo in hormone-sensitive and hormone-refractory prostate cancer (79). EGF is a strong chemoattractant for prostate cancer cells. Blocking the EGFR receptor with C225 in vitro decreases migration of prostate cancer cells in a dose-dependent manner by decreasing phosphorylation of the EGFR (80). C225 has also been shown to cause cell cycle arrest and decrease proliferation of prostate cancer cells (81, 82). The binding of C225 to the EGFR results in multiple events that decrease proliferation and possibly metastatic potential in prostate cancer. It has also been shown to inhibit the expression of VEGF and vascular permeability factor, both of which are involved in the induction of angiogenesis (59). Phase I clinical trials of C225 alone or in combination with cisplatin have been conducted in patients with cancers overexpressing EGFR (83). Skin toxicity in the form of ushing, seborrheic dermatitis, and acneiform rash were observed at doses higher than 100 mg/m2. The rash commonly presents on the head, neck, and trunk and resolves without scarring once the treatment has been discontinued (84). Epiglottitis resulting in severe shortness of breath was noted when C225 was combined with cisplatin at 100 mg/m2, but not at 60 mg/m2 (83). Another phase I study, in which patients with recurrent head and neck cancer received cisplatin every three weeks and C225 weekly, found no such toxicity (85). Of the 9 evaluable patients in that study, 2 patients previously treated with cisplatin had complete responses and an additional 4 had partial responses. In addition, tumor
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biopsies demonstrated a dose-dependent saturation of the EGFR and loss of EGFR tyrosine kinase activity following repeated doses of the antibody. Phase III trials are now evaluating the impact of adding C225 to cisplatin in patients with recurrent or metastatic head and neck cancer and the benet of adding C225 to radiation therapy in patients with locally advanced head and neck cancer. Studies are also ongoing in patients with nonsmall-cell lung cancer, who receive C225 along with various chemotherapy regimens including carboplatin and paclitaxel, gemcitabine and carboplatin, and docetaxel (84). ABX-EGF, another antibody that targets EGFR, is also under clinical development. This antibody was produced in a transgenic mouse in which murine antibody genes were inactivated and replaced by genes that encode the human sequences (86). The resulting fully human antibody has been shown to cause inhibition of the tyrosine phosphorylation of the receptor and internalization of the receptor. The inhibitory concentration of the antibody is lower than that of MAb225, the parent antibody of C225. Preclinical studies in animals have shown eradication of EGFR tumors with ABX-EGF antibody therapy alone, whereas similar studies with C225 have required the addition of chemotherapy to produce similar results (87). ABX-EGF is currently in clinical trials.
Ep-CAM (EGP-2/GA 733-2)

The 17-1A antibody, which recognizes Ep-CAM, has undergone extensive clinical testing, with some studies suggesting efcacy in colorectal carcinomas. The murine antibody has been replaced by a human chimeric construct that offers increased mononuclear cell-mediated ADCC (88), a longer half-life, no development of human antimouse antibody (HAMA), and radiolocalization to known sites of disease (89). Clinical trials have also incorporated cytokines because of in vitro data that demonstrate improved target cell killing by apoptosis with interferon- (90) and increased ADCC with interferon- (91), GM-CSF (92, 93), the combination of GM-CSF and interleukin (IL)-2 (94), IL-4 (95), and IL-8 (96). These studies have formed the basis for clinical trials incorporating the antibody and cytokines such as interferon- (97) and GM-CSF (98). Although these studies have shown evidence for cytokine immunomodulation, no consistent pattern of clinical benet has emerged from therapy with these combinations. The therapeutic use of 17-1A has also been shown to induce potentially effective anti-idiotypic antibodies (99101), an effect that was increased by concomitant therapy with GM-CSF (102), and to increase inltration of macrophages and of CD4+ and CD8+ T cells within tumors (103). Induction of T cells against antiidiotypic epitopes has also been evaluated (104). Five of ten patients with antiidiotypic antibodies were also found to have induction of EP-CAM antigen-specic T cells. Four of these patients showed a clinical response and their T cells demonstrated a proliferative response in vitro when stimulated with an anti-idiotypic antibody, in contrast to the six patients without evidence of T cells against antiidiotypic epitopes.
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Initial phase I studies with 17-1A yielded promising results. Several studies demonstrated responses in patients with metastatic cancers of the gastrointestinal tract with only one intravenous dose of antibody. One patient received an intrahepatic infusion of autologous mononuclear cells mixed with 17-1A, which resulted in regression of hepatic metastases. Antibody therapy was well tolerated with mild nausea, vomiting, or diarrhea. Phase II studies in colon and pancreatic cancers were less encouraging (105, 106). Repeat-dose injections and combinations with cytokines to enhance effector cell number and activity did not result in signicant response rates, although in vitro assays of patient effector cells revealed increased activity with cytokine therapy. Repeat-dose schedules with higher doses were theorized to induce tolerance to the murine antibody, but this maneuver had no signicant impact on clinical response (106). Some trials reported evidence of induction of anti-idiotypic antibodies, correlating with clinical response in one trial. The overall lack of efcacy seen in these studies may have resulted from the large tumor burden or the associated immunosuppression in these patients with metastatic disease. The initial study evaluating 17-1A in the adjuvant setting suggested possible efcacy. A phase III clinical trial of patients with lymph-nodepositive colorectal cancer randomized patients to observation or therapy with 17-1A. The surgical approach was standardized and agreed to by all participating surgeons. All patients were followed post-operatively in a similar manner, irrespective of treatment. Of 189 patients, 166 were evaluable for overall survival and disease-free survival. Therapy with 17-1A was well tolerated except for malaise, low-grade fevers and chills, and mild gastrointestinal discomfort. Four anaphylactic reactions were treated without sequelae. At ve years of follow-up, the death rate was 36% in the 17-1A group in contrast to 51% in the observation group, and the calculated recurrence rate was 48.7% versus 66.5% (107). At seven years the death rates were 43% (17-1A) and 63% (observation), and the calculated recurrence rates were 52% and 68%, respectively, demonstrating a continued benet in patients who received 17-1A (108). Treatment with 17-1A was associated with a decreased incidence of metastatic disease but did not alter the incidence of local failure. This shift in failure pattern was felt to represent the ability of 17-1A to eradicate isolated metastatic cancer cells but not bulkier disease. Alternatively, altered vasculature due to surgery and scar tissue may have limited antibody diffusion to tumor cells. Another factor potentially accounting for the apparent lack of efcacy of 17-1A on local control is that 11 patients in the observation group received pre- or postoperative radiation therapy alone or in combination with chemotherapy. This trial has been criticized because of higher rates of recurrence and death in the control arm than would be anticipated. However, it is intriguing because it demonstrates an effect of antibody-based therapy in the adjuvant setting of colorectal cancer. Recent clinical trials were designed to conrm these results in stage II colon cancers and to test the value of adding 17-1A to standard chemotherapy in patients with stage III disease. Therapy with antibody alone is unlikely to be effective in all patients owing to the antigenic heterogeneity of cancer cells. Combining standard
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adjuvant therapy with 17-1A would introduce therapies that have different mechanisms of action, are cell-cycledependent and -independent, and allow death of cancer cells irrespective of antigen expression patterns. A preliminary report of the phase III trial of 17-1A versus no therapy in the adjuvant setting revealed no difference in overall survival in patients with stage II colorectal at a median follow up of 13.4 months (109); a randomized study of chemotherapy with or without the antibody in patients with stage III disease has shown a minimal benet of questionable signicance in a preliminary analysis. Overall survival was 81.6% for combination therapy versus 78.9% for chemotherapy alone; this was not a statistically signicant difference. Irrespective of the nal analyses of these large studies, the value of treating colorectal cancer patients with this antibody is unproven and likely to be low.
Vascular Endothelial Growth Factor

Molecules that are selectively expressed in the tissue matrix surrounding tumor are potentially important targets for antibody therapy. The rst of these targets to be exploited resides in the vasculature that feeds tumor cells. Bevacizumab is a humanized MAb that blocks binding of the vascular endothelial growth factor (VEGF) to its receptor on vascular endothelium. VEGF is produced by many cancers to stimulate the growth of new blood vessels, and in some studies its expression at tumor sites is correlated with risk for metastases. A phase I clinical study of bevacizumab tested doses of 0.110 mg/kg infused on days 1, 28, 35, and 42 (110). No severe toxicities were found. At doses of 310 mg/kg, increases in systolic and diastolic blood pressure of >10 mm Hg were noted during therapy (110), and subsequent studies have conrmed that hypertension is a toxicity of this agent (111). Two patients receiving 3 mg/kg experienced bleeding into their tumors. One patient with hepatocellular carcinoma bled into a previously undiagnosed brain metastasis. Another patient with an extremity sarcoma and lung metastases bled into the extremity mass and experienced hemoptysis. In a phase II study of bevacizumab combined with carboplatin and paclitaxel in patients with nonsmall-cell lung cancer, 6 of 66 patients developed pulmonary hemorrhage, 4 of whom died (112). Patients with squamous cell lung cancers and tumors with evidence of cavitation or squamous cell histology appeared to be at higher risk of hemoptysis. Interestingly, a study of bevacizumab and chemotherapy in metastatic colorectal cancer found an increase in thrombotic episodes as well as hemorrhage. The incidence of thrombotic events was higher at the 5 mg/kg dose level than at the 10 mg/kg dose level. The majority of cases were deep venous thromboses, but one cerebral vascular accident and one pulmonary embolism were reported. Clinical trials have suggested a therapeutic benet from bevacizumab. Although the phase I study demonstrated no objective responses, 12 of 23 patients had stable disease during the trial (70 days) and an additional patient with renal cell carcinoma experienced a minor response (110). A phase II study was conducted
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in 25 women whose metastatic breast cancer had progressed following at least one anthracycline or taxane-based regimen. Clinical responses were noted at doses of 3 mg/kg (n = 1/18) and 10 mg/kg (n = 2/17) (111). All responses were in lymph nodes or subcutaneous skin nodules. Bevacizumab has also been combined with chemotherapy in patients with nonsmall-cell lung cancer (113) and metastatic colorectal cancer (114). The response rate and time to progression in patients with lung cancer improved when carboplatin and paclitaxel were combined with bevacizumab at 10 mg/kg, but not at 5 mg/kg. A similar result was found in patients with colorectal cancer receiving 5-uorouracil and folinic acid plus bevacizumab, but the improved response rate was seen at the 5 mg/kg dose. Time to progression improved at the both 5 mg/kg and 10 mg/kg, but to a greater extent at 5 mg/kg.
RADIOIMMUNOTHERAPY Radioimmunoconjugates
A tumor-specic antibody that does not alter tumor growth properties can be armed with a radioisotope to create a cytotoxic agent. Even antibodies that are effective antitumor agents in an unconjugated state can have enhanced efcacy with the addition of a cytotoxic radioisotope. For example, although therapy with the anti-CD20 MAb rituximab is associated with a signicant antitumor effect in patients with non-Hodgkins lymphoma, signicantly more patients exhibit complete responses when the 90Y parent MAb Y2B8 is added to the treatment protocol (115). The recent availability of a panel of antibody-based constructs with a range of in vivo half-lives now makes it possible to select antibody/radioisotope combinations with matched biologic and physical half-lives. This type of pairing enables the majority of the decay, and therefore cytotoxic emissions, to occur while the greatest quantity of labeled antibody is localized in the tumor. Williams et al. developed formulas, termed the imaging gure of merit (IFOM) and therapy gure of merit (TFOM), to determine which isotopes best pair with a series of antibodies and fragments based on the rate of MAb clearance, isotope half-life, and emission track length (116). This approach can be used to optimize the efciency and specicity of an imaging or treatment system. Until recently, most RAIT studies employed 131I, but improvements in labeling strategies and the availability of large quantities of radiopharmaceutical-grade 90Y have enabled the study of 90Y conjugates. Now, a wide variety of therapeutic radioisotopes are available for RAIT. They fall into two general categories, those that emit shorttrack-length (e.g., one cell length) alpha particles with a high linear energy transfer (LET) and those that emit longertrack-length (e.g., 50 cell lengths) beta particles with a low LET. Because the LET is a measure of the energy deposited along the track of the emitted particle, a high LET is associated with a greater probability of tumor cell death. This is in part dictated by the difference in the size of the particles. An alpha particle is equivalent to a helium nucleus whereas a beta particle is an electron. Alpha particles tend to kill cells by causing
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irreparable double-strand DNA breaks; beta particles lead to single-strand DNA breaks. Of the available beta-emitting radioisotopes, 90Y (t1/2 = 64 h) is rapidly gaining dominance in most RAIT protocols owing to its ease of labeling and absence of a gamma emission. The other commonly used radionuclide, 131I (t1/2 = 8.02 days), requires a trained radiopharmacist and appropriately shielded/vented radiopharmacy because of its volatile nature. Other beta-emitting radioisotopes that have shown promise for radioimmunotherapy include 67Cu (t1/2 = 61.8 h) and 177Lu (t1/2 = 6.73 days). There are also a number of alpha-emitting radioisotopes that are potential partners with antibody-based molecules for RAIT. These include 213Bi (t1/2 = 45 min), 212Bi (t1/2 = 61 min), and 211At (t1/2 = 7.2 h). Whereas the half-life of 211At is compatible with the pharmacokinetics of several engineered antibody-based molecules, the very short half-lives of the bismuth radioisotopes limit their utility to the setting of disseminated disease or to pretargeted RAIT (described below). Some clinical trials have demonstrated partial, short-lived clinical responses in some patients with advanced, solid tumors, but most of the signicant advances in RAIT have occurred in the treatment of hematologic neoplasms. Lymphomas and leukemias remain the most sensitive tumor targets for RAIT, presumably because of their intrinsic sensitivity to radiation and the relatively good access of radioimmunoconjugates to the malignant cells that comprise these neoplasms. Patients with hematologic neoplasms are also less likely to mount HAMA responses when foreign MAbs are employed.
Radioimmunotherapy for Hematologic Malignancies

The CD20 antigen has been a very effective target for RAIT. Press and colleagues used high, marrow-ablative doses of 131I-B1 (tositumomab or Bexxar ) anti-CD20 RAIT in the setting of autologous bone marrow transplantation. In a total of 42 patients with chemotherapy-refractory lymphomas, 24 exhibited MAb distributions that were predictive of a favorable response and 19 received highdose RAIT. Of the RAIT group, 84% exhibited a complete remission, and 11% had a partial remission (117). Many of the complete remissions observed with this approach have proven to be durable, with 62% exhibiting progression-free survival at 2 years. Low-dose, non-myeloablative RAIT with 131I-B1 has also proven efcacious, showing 50% response rates, with a median duration of 16.5 months, in patients with chemotherapy-refractory B cell lymphoma (118, 119). Preliminary studies have also shown that RAIT may be useful as a conditioning regimen prior to bone marrow transplantation in patients with acute myelogenous leukemia (120).
B-1
Ibritumomab tiuxetan (Zevalin ) is another MAb that targets an epitope on the CD20 antigen that is distinct from the B1 epitope. Another distinction between the ibritumomab trials and the tositumomab trials described above is that Ibritumomab employs 90Y in place of 131I. This antibody is the rst, and to date only, MAb licensed for use in RAIT in the United States.
IBRITUMOMAB TIUXETAN
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A number of clinical trials have evaluated ibritumomab in over 230 patients with relapsed or refractory low- or intermediate-grade non-Hodgkins lymphoma (reviewed in Reference 121). The most comprehensive study was a randomized phase III trial that compared the safety and efcacy of a single dose of ibritumomab with a standard treatment course of rituximab in 143 patients with low-grade, follicular or transformed non-Hodgkins lymphoma. In this trial, an overall response rate of 80% and a complete response rate of 30% was observed in the group treated with ibritumomab versus an overall response rate of 56% and a complete response rate of 16% in the group treated with rituximab (122).
LYM-1 Lym-1 is specic for a human leukocyte antigen (HLA-DR) expressed in >95% of B cell tumors. This murine MAb has not been humanized. In phase I/II clinical trials, 131I-Lym-1 has shown signicant antitumor activity. Low-dose, fractionated treatment of 30 patients (25 with non-Hodgkins lymphoma and 5 with chronic lymphocytic leukemia) resulted in 3 complete responses and 14 partial responses (123). When treated at the non-myeloablative maxiumum tolerated dose of 100 mCi/m2, 11 of 21 patients responded favorably (7 complete responses, 4 partial responses) (124).
The cell surface antigen CD33 is expressed on most myeloid leukemic blasts and leukemic progenitor cells. Its normal tissue expression is limited to committed normal myelomonocytic and erythroid progenitor cells and (at low levels) early hematopoietic stem cells. M195, a murine anti-CD33 MAb, has been used to deliver therapeutic doses of 131I in combination with busulfan or cyclophosphamide to eliminate disease before bone marrow transplantation (125). HuM195, a humanized version of M195, has been employed as a vehicle for the RAIT of acute and chronic myelogenous leukemia. HuM195 RAIT resulted in minor responses in 8 of 12 patients treated with 90Y-conjugated Mab and 13 of 18 patients treated with 213Bi-conjugated Mab (126, 127). The 213Bi studies were the rst use of alpha particles in RAIT.
M195
Radioimmunotherapy of Solid Malignancies

Signicantly less progress has been made in the treatment of solid malignancies with RAIT. In most reported trials in patients with solid tumors (e.g., breast carcinoma, colon carcinoma, ovarian carcinoma), RAIT is associated with, at best, stable disease. Although reports of a greater response do appear, their rarity gives them the aura of an Elvis sighting. A phase II trial of 75 mCi/m2 of 131I-labeled CC49 MAb with interferon (to enhance target antigen expression) in patients with metastatic prostate cancer reported minor radiographic responses and relief of pain (128). Similar results were reported for a phase I study of 90Y-2IT-BAD-M170 in patients with androgen-independent metastatic prostate cancer (129). In a recent phase I trial in patients with recurrent or persistent ovarian cancer, intraperitoneal 177 Lu-labeled CC49 MAb, plus interferon and Taxol led to partial responses in 4 of 17 treated patients and progression-free intervals in patients without measurable
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disease (130). Transient clinical responses were also observed in a phase I trial in metastatic breast cancer patients treated with 90Y-BrE-3 (131). Still, several new agents are currently undergoing clinical evaluation, many of which have novel characteristics (e.g., domain deletions or signicant antitumor properties as a naked MAb) that may translate into improved results.
Pretargeted Radioimmunotherapy
One new RAIT strategy recently examined in the clinic is pretargeted radioimmunotherapy (PRIT). PRIT differs from traditional RAIT in that the antibody and the radioisotope are delivered to the tumor in separate steps. In the PRIT protocols employed to date, MAb-streptavidin (MAb-SA) or MAb-biotin (MAb-B) conjugates were administered to the patient. After the MAb conjugate localized in the tumor, a clearing agent [e.g., a biotingalactosehuman serum albumin conjugate or streptavidin (SA)] is administered that binds to the circulating MAb conjugate and directs its clearance by the liver. After an additional 24 h, a biotin-chelate-90Y complex is administered that binds specically to the MAb-SA or MAB-B-SA prelocalized in the tumor. PRIT clinical trials have been performed in patients with glioma (132), colon cancer (133), prostate cancer, and non-Hodgkins lymphoma (134). Of 48 glioma patients treated by PRIT at doses of 6080 mCi/m2, 25% (12 patients) exhibited a reduction in tumor mass ranging from >25% to 100%, with 8 responses lasting longer than one year (132). In the PRIT treatment of patients with colon cancer, 8% (2 of 25) of the patients treated with pretargeted NR-LU-10 MAb and 110 mCi/m2 of 90Y-DOTA-biotin had a partial response, and 16% (4 of 25) exhibited stable disease. However, signicant hematologic and nonhematologic toxicities (diarrhea) were reported (133). A companion trial directed against prostate cancer revealed similar toxicities (I. Horak, personal communication). Signicantly more success was observed in the PRIT of non-Hodgkins lymphoma. In this trial, rituximab, which has antitumor properties in an unconjugated form, was conjugated to SA as the rst-step reagent. Six of seven patients treated with doses of 30 or 50 mCi/m2 of 90Y-DOTA-biotin exhibited objective regressions, with one partial response and three complete responses (134). The toxicities reported in this trial were also less severe and were limited to grade I/II nonhematologic toxicity and transient grade III hematologic toxicity.
CONCLUSIONS
Therapeutic antibodies have made the transition from concept to clinical reality over the past two decades. Many are now being tested as adjuvant or rst-line therapies to assess their efcacy in improving or prolonging survival. Modied antibody structures, such as bispecic antibodies or smaller antibody fragments, have yet to claim dened therapeutic roles, whereas radioimmunotherapy has clearly demonstrated efcacy in some disease settings.
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The Annual Review of Medicine is online at http://med.annualreviews.org
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Annual Review of Medicine Volume 54, 2003
CONTENTS
TECHNOLOGY-DRIVEN TRIAGE OF ABDOMINAL TRAUMA: THE EMERGING ERA OF NONOPERATIVE MANAGEMENT, D. Demetriades
and G. Velmahos
1 17
ANGIOGENESIS IN ISCHEMIC AND NEOPLASTIC DISORDERS,

Gregg L. Semenza
PATHOGENESIS AND TREATMENT OF GRAFT-VERSUS-HOST DISEASE AFTER BONE MARROW TRANSPLANT, Georgia B. Vogelsang,
Linda Lee, and Debra M. Bensen-Kennedy 29 53 73 89 113
UPDATE IN PALLIATIVE MEDICINE AND END-OF-LIFE CARE,

Janet L. Abrahm
MOLECULAR GENETICS OF LUNG CANCER, Yoshitaka Sekido,

Kwun M. Fong, and John D. Minna
PATHOPHYSIOLOGICAL-BASED APPROACHES TO TREATMENT OF SICKLE CELL DISEASE, Martin H. Steinberg and Carlo Brugnara NEW CONCEPTS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE,
Peter J. Barnes
CALORIE RESTRICTION, AGING, AND CANCER PREVENTION: MECHANISMS OF ACTION AND APPLICABILITY TO HUMANS,
Stephen D. Hursting, Jackie A. Lavigne, David Berrigan, Susan N. Perkins, and J. Carl Barrett ERECTILE DYSFUNCTION, Ridwan Shabsigh and Aristotelis G. Anastasiadis 131 153 169 185 197 217 235 v
THE HYPEREOSINOPHILIC SYNDROME REVISITED, Florence Roufosse,

Elie Cogan, and Michel Goldman
STANDARDS OF CARE IN GERIATRIC PRACTICE, Robert J. Luchi,

Julie K. Gammack, Victor J. Narcisse, III, and C. Porter Storey, Jr.
NEW CONCEPTS IN THE TREATMENT OF RHEUMATOID ARTHRITIS,

Raphaela Goldbach-Mansky and Peter E. Lipsky
STUDYING CANCER FAMILIES TO IDENTIFY KIDNEY CANCER GENES,

Berton Zbar, Richard Klausner, and W. Marston Linehan
THE AUTOMATED EXTERNAL DEFIBRILLATOR: CRITICAL LINK IN THE CHAIN OF SURVIVAL, Karthik Ramaswamy and Richard L. Page
vi
CONTENTS
THE BIOMEDICAL CHALLENGES OF SPACE FLIGHT, David R. Williams GENETICS AND ARRHYTHMIAS, Robert Roberts and Ramon Brugada OPEN SURGICAL REPAIR VERSUS ENDOVASCULAR THERAPY FOR CHRONIC LOWER-EXTREMITY OCCLUSIVE DISEASE,
Marc L. Schermerhorn, Jack L. Cronenwett, and John C. Baldwin AIDS-RELATED MALIGNANCIES, David T. Scadden
245 257
269 285
DIAGNOSIS AND PREVENTION OF BOVINE SPONGIFORM ENCEPHALOPATHY AND VARIANT CREUTZFELDT-JAKOB DISEASE,
David N. Irani and Richard T. Johnson
305 321 343
ATHEROPROTECTIVE EFFECTS OF HIGH-DENSITY LIPOPROTEINS,

Gerd Assmann and Jerzy-Roch Nofer
MONOCLONAL ANTIBODY THERAPY FOR CANCER, Margaret von

Mehren, Gregory P. Adams, and Louis M. Weiner
FUNCTIONAL GENOMICS OF THE PARAOXONASE (PON1) POLYMORPHISMS: EFFECTS ON PESTICIDE SENSITIVITY, CARDIOVASCULAR DISEASE, AND DRUG METABOLISM,
Lucio G. Costa, Toby B. Cole, Gail P. Jarvik, and Clement E. Furlong GENETIC PRIVACY, Pamela Sankar THE ANTIPHOSPHOLIPID SYNDROME, Jacob H. Rand 371 393 409 425 437 453 473 491 513 535
ANTI-INTEGRIN THERAPY, Christian W. Hamm PHARMACOGENETICS IN CANCER TREATMENT, R. Nagasubramanian,

F. Innocenti, and M.J. Ratain
GENETICS AND PATHOPHYSIOLOGY OF HUMAN OBESITY,

David E. Cummings and Michael W. Schwartz
MOLECULAR GENETIC RISK SCREENING, Wayne W. Grody THE CURRENT STATUS OF HEMATOPOIETIC CELL TRANSPLANTATION,
Frederick R. Appelbaum
GROWTH HORMONE THERAPY IN ADULTS, David E. Cummings

and George R. Merriam
THE INFLUENCE OF HLA GENOTYPE ON AIDS, Mary Carrington

and Stephen J. OBrien
INDEXES
Subject Index Cumulative Index of Contributing Authors, Volumes 5054 Cumulative Index of Chapter Titles, Volumes 5054 553 585 589
ERRATA
An online log of corrections to Annual Review of Medicine chapters may be found at http://med.annualreviews.org/errata.shtml

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Annu. Rev. Med. 2003. 54:34369 doi: 10.1146/annurev.med.54.101601.152442 Copyright c 2003 by Annual Reviews.

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MONOCLONAL ANTIBODY THERAPY FOR CANCER

IMMUNOGLOBULIN STRUCTURE IgG

DESIRABLE CHARACTERISTICS OF ANTIBODY TARGETS

MECHANISMS OF ACTION FOR ANTIBODIES AS THERAPEUTIC AGENTS

Hematologic Malignancy Antigens

Solid Tumor Antigens

Epidermal Growth Factor Receptor

Ep-CAM (EGP-2/GA 733-2)

Vascular Endothelial Growth Factor

Radioimmunotherapy for Hematologic Malignancies

Radioimmunotherapy of Solid Malignancies

The Annual Review of Medicine is online at http://med.annualreviews.org

Annual Review of Medicine Volume 54, 2003

ANGIOGENESIS IN ISCHEMIC AND NEOPLASTIC DISORDERS,

UPDATE IN PALLIATIVE MEDICINE AND END-OF-LIFE CARE,

MOLECULAR GENETICS OF LUNG CANCER, Yoshitaka Sekido,

THE HYPEREOSINOPHILIC SYNDROME REVISITED, Florence Roufosse,

STANDARDS OF CARE IN GERIATRIC PRACTICE, Robert J. Luchi,

NEW CONCEPTS IN THE TREATMENT OF RHEUMATOID ARTHRITIS,

STUDYING CANCER FAMILIES TO IDENTIFY KIDNEY CANCER GENES,

305 321 343

ATHEROPROTECTIVE EFFECTS OF HIGH-DENSITY LIPOPROTEINS,

MONOCLONAL ANTIBODY THERAPY FOR CANCER, Margaret von

ANTI-INTEGRIN THERAPY, Christian W. Hamm PHARMACOGENETICS IN CANCER TREATMENT, R. Nagasubramanian,

GENETICS AND PATHOPHYSIOLOGY OF HUMAN OBESITY,

GROWTH HORMONE THERAPY IN ADULTS, David E. Cummings

THE INFLUENCE OF HLA GENOTYPE ON AIDS, Mary Carrington

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