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Improving the Efficacy of Antibody-Based Cancer Therapies

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Improving the Efficacy of Antibody-Based Cancer Therapies REVIEWS IMPROVING THE EFFICACY OF ANTIBODY-BASED CANCER THERAPIES Paul Carter A quarter of a century after their advent, monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies. PHAGE DISPLAY Antibodies are finally realizing their potential as anti- relapsed low-grade non-Hodgkin’s lymphoma,only Technology for displaying a cancer therapeutics: since 1995, five antibodies have about half of the patients responded7. This included protein (or peptide) on the been approved for the treatment of cancer (TABLE 1). 6% COMPLETE and 42% PARTIAL RESPONSES from 166 surface of a bacteriophage, Additional approvals will surely follow from among patients, similar results to those obtained with a single- which contains the gene(s) 1,2 that encodes the displayed the 20 or so antibodies now in oncology trials , agent cytotoxic chemotherapeutic in this group of protein(s), thereby physically including 10 that have advanced to Phase III trials or patients. These data, combined with the mild toxicity linking the genotype and further (TABLE 1). profile of Rituxan, led the United States Food and Drug phenotype. The emergence of antibodies as therapeutics was Administration (FDA) to approve Rituxan for relapsed VALENCY made possible by the advent of technologies designed to indolent lymphoma. Unfortunately, the median 7 For antibody-derived overcome the main limitations of mouse monoclonal RESPONSE DURATION was only about 12 months . In a Phase molecules, this refers to the antibodies (mAb) — immunogenicity of these foreign III study of trastuzumab (Herceptin) — a humanized number of binding sites for the proteins in patients, inefficient effector functions (see mAb against the receptor tyrosine kinase ERBB2 (also cognate antigen(s). below) and half-lives that are typically less than 20 known as HER2/NEU)8 — in metastatic breast cancer, 1–4 COMPLETE RESPONSE hours . These core technologies, in historical order of the OVERALL RESPONSE RATE was only 15%: 8 complete and No remaining tumour can be development, are chimerization and humanization of 26 partial responses were observed in 222 patients9.The detected by visual inspection or mouse antibodies, and direct routes to high-affinity median response duration and survival were 9.1 and 13 by clinical imaging technologies. human antibodies using PHAGE DISPLAY libraries or trans- months, respectively9. This does not mean that the disease has been cured. genic mice (BOX 1). Beyond these core technologies, All clinically approved and most experimental anti- remarkable progress has been made in engineering anti- body drugs directly target tumour cells. Several strategies PARTIAL RESPONSE bodies with modified properties — for example, molecu- are being explored to increase the efficacy of such antibod- ≥ 50% reduction in tumour with lar size, antigen-binding affinity, specificity and VALENCY1,3–5. ies, including enhancement of effector functions, direct no new lesions or increase in size Tumour targeting by antibodies with engineered prop- and indirect arming, and pre-targeting of prodrugs or of an existing lesion. erties is in its infancy, but holds much promise for radionuclides (FIG. 1). In addition, potent antitumour enhancing the antitumour activity of antibodies (BOX 2). activity might be achieved with antibodies that prevent Important advances in antibody technologies soluble growth factors from binding to their cognate notwithstanding (BOXES 1 and 2), patient tumour- receptors, such as the epidermal-growth-factor receptor Immunex, 51 University response data show the urgent need to enhance the effi- (EGFR)10 and ERBB211,12. Promising and potentially com- Street, Seattle, Washington 98101, USA. cacy of the current generation of anticancer antibodies. plementary alternative strategies to direct tumour target- e-mail: For example, in a Phase II study of the chimeric anti- ing include targeting tumour vasculature, angiogenic [email protected] CD20 antibody6 rituximab (Rituxan), in patients with growth factors and their receptors (BOX 3)5. 118 | NOVEMBER 2001 | VOLUME 1 www.nature.com/reviews/cancer © 2001 Macmillan Magazines Ltd REVIEWS Table 1 | Antibodies in advanced oncology trials* Antibody trade Antigen target Antibody type Strategy to enhance Tumour target Status Corporate name activity of naked sponsors (generic name) antibody Avastin VEGF hu IgG1 Combination with Metastatic NSCLC, Phase III, Genentech (bevacizumab) chemotherapy metastatic CRC Phase III BEC2 Anti-idiotypic mAb, mu IgG Vaccine SCLC, malignant Phase III, ImClone (mitumomab) GD3 ganglioside melanoma Phase II Systems, mimic Merck KGaA 131 Bexxar CD20 mu IgG2a iodine NHL BLA filed Corixa, (tositumomab) with US FDA GlaxoSmith- Kline Campath CD52 hu IgG1 None B-cell CLL Approved in US Millennium (alemtuzumab) May 2001 and ILEX Partners CeaVac Anti-idiotypic mu IgG Vaccine in combination CRC Phase III, Titan mAb, CEA mimic with chemotherapy for NSCLC Phase II Pharma- CRC or TriAb for NSCLC ceuticals Herceptin ERBB2 hu IgG1 Combination with Metastatic breast Approved in US Genentech (trastuzumab) chemotherapy cancer overexpressing September 1998 ERBB2 IMC-C225 EGFR ch IgG Combination with CRC, locally advanced BLA filing in mClone (centuximab) chemotherapy or or metastatic head progress, Systems external beam and neck Phase III radiation LymphoCide CD22 hu IgG None NHL Phase III Immunomedics (epratuzumab) MDX-210 ERBB2 mu F(ab’)2 Bispecific Ovarian cancer Phase III Medarex, X CD64 (FcγRI) overexpressing Immuno ERBB2 Designed Molecules Mylotarg CD33 hu IgG4 Calicheamicin AML Approved in US Wyeth (gemtuzumab conjugate May 2000 Laboratories ozogamicin) Panorex EpCam mu IgG2a Combination with Dukes’ C CRC Approved in GlaxoSmith- (edrecolomab) chemotherapy Germany Kline, January 1995 Centocor Rituxan CD20 ch IgG1 Combination with NHL Approved in US IDEC (rituximab) chemotherapy November 1997 Pharma- ceuticals, Genentech 90 Theragyn PEM mu IgG1 yttrium Ovarian cancer, Phase III, Antisoma (pemtumomab) gastric cancer Phase II Zamyl CD33 hu IgG1 Combination with AML Phase III Protein Design chemotherapy Labs 90 Zevalin CD20 mu IgG1 yttrium NHL BLA filed with IDEC (ibritumomab US FDA Pharma tituxetan) ceuticals * Phase III clinical trials or later. Not included are ongoing trials with marketed antibody products. Every effort has been made to obtain reliable data from several sources (company and industry web sites, and REFS 1,2), but accuracy cannot be guaranteed. AML, acute myelogenous leukaemia; BLA, Biologics License Application; CEA, carcino-embryonic antigen; ch, chimeric; CLL, chronic lymphocytic leukaemia; CRC, colorectal cancer; EpCam, epithelial cellular-adhesion molecule; FDA, Federal Drug Administration; EGFR, epidermal-growth-factor receptor; hu, humanized; mAb, monoclonal antibody; Ig, immunoglobulin; mu, murine; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer; PEM, polymorphic epithelial mucin; SCLC, small-cell lung cancer; VEGF, vascular endothelial growth factor. Clinical strategies used in combination with cisplatin and carboplatin13,14, Combination with cytotoxic drugs. Combining different and additive benefit when used in conjunction with cytotoxic drugs is a widely and successfully used clinical doxorubicin, cyclophosphamide, methotrexate, taxol or strategy in oncology that increases the response rate and the selective cyclooxygenase-2 inhibitor, celecoxib14–18. RESPONSE DURATION duration of individual drugs. The use of antibodies in The addition of Herceptin to a cytotoxic chemotherapy Time from the first response conjunction with chemotherapeutics is a natural exten- regimen was associated with statistically significant bene- until disease progression or sion of this approach, and is strongly supported by pre- fits in a Phase III trial in ERBB2-overexpressing meta- death. clinical TUMOUR XENOGRAFT studies that show improved static breast cancer19. These gains included longer median OVERALL RESPONSE RATE efficacy of antibody and chemotherapeutic combinations duration of response (9.1 versus 6.1 months), higher Sum of partial and complete compared with each drug used in isolation. For example, overall response rate (50% versus 32%) and lower death responses. Herceptin has synergistic antitumour activity when rate at one year (22% versus 33%). NATURE REVIEWS | CANCER VOLUME 1 | NOVEMBER 2001 | 119 © 2001 Macmillan Magazines Ltd REVIEWS Box 1 | Key therapeutic antibody technologies Murine antibodies Derived by hybridoma technology99 following immunization of mice or, less commonly, rats. Chimeric antibodies Obtained by joining the antigen-binding variable domains of a mouse monoclonal antibody (mAb) to human constant domains: mouse VL to human 100,101 CL and mouse VH to human CH1–CH2–CH3 for light and heavy chains, respectively . Humanized antibodies In the simplest case, these are created by grafting the antigen-binding loops, known as complementarity-determining regions (CDRs), from a mouse mAb into a human IgG102–104. The generation of high-affinity humanized antibodies generally requires the transfer of one or more additional residues from the so-called framework regions (FRs) of the mouse parent mAb. Several variants of the humanization technology have been developed105. Human antibodies These have high affinity for their respective antigens and
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