Educational Forum

Monoclonal antibodies: Targeted therapytherapy N. Gupta, A. Srivastava

ABSTRACT

In an ongoing quest to improve the therapeutic arsenal against cancer, a fourth weapon Intas Biotechnology/Oncology, Plot other than surgery, and radiotherapy has emerged, i.e. targeted therapy. No. 423/P/A/GIDC, Sarkhej Bavla Targeted therapy includes, tyrosine kinase receptor inhibitors (small molecule inhibitors Highway, Moraiya, Tal: Sanand, Ahmedabad-382 210. India like imatinib, gefitinib, erlotinib), angiogenesis inhibitors (bevacizumab), proteasome inhibitors (bortezomib), biological response modifiers (denileukin diftitox) and Received: 2.2.2006 monoclonal antibodies (MAbs). The remarkable specificity of MAbs as targeted therapy Revised: 3.3.2006 makes them promising agents for human therapy. Not only can MAbs be used Accepted: 6.6.2006 therapeutically to protect against disease, they can also be used to diagnose a variety of illnesses, measure serum protein and drug levels, type tissue and blood and identify Correspondence to: infectious agents and specific cells involved in immune response. About a quarter of all Neera Gupta biotech drugs in development are MAbs, and about 30 products are in use or being E-mail: investigated. As a majority of the MAbs are used for the treatment of various [email protected] hematological and nonhematological malignancies, their role in cancer is discussed. KEY WORDS: Antibodies, chemotherapy, immunity, malignancy. .com).

Introduction 1. Tyrosine kinase receptor inhibitor: There are different types of tyrosine kinase receptors in the body, one family being ‘Targeted therapy’ is a general term that refers to a the human epidermal receptor (HER) family. or drug that targets a specific pathway by attacking The members of the family are: or blocking important targets. The targets themselves are.medknow HER1 (also called as epidermal growth factor receptor typically various molecules (or small particles) in the body that [EGFR]) are known or suspected to play a role in various diseases. HER2 (also called ErbB2 or HER2/neu) One long-held dream is that the specificity of immune HER3 (also called ErbB3) mechanisms could be harnessed against tumor(www cells. HER4 (also called ErbB4) Monoclonal antibodies (MAbs) are so called because they arise EGFR inhibitors include small molecule inhibitors: gefitinib from a single cell type. They act by recognizing the protein on for non-small cell lung cancer and erlotinib for metastatic the surface of the cellThis and then PDFa lock site onto is hostedit. available They are produced by forMedknow freerenal download cell Publications carcinoma. from in the laboratory from a single clone and recognize only one Imatinib, the first commercially available tyrosine kinase antigen. MAbs are typically made by fusing a normally short- inhibitor for clinical use which targets platelet derived lived antibody producing β-cell to a rapidly dividing cell, such growth factor receptor (PDGF-R), was found to inhibit a as cancer cell (often referred to as ‘immortal cell’). The constitutively active fusion product arising from the resulting hybrid cell, or hybridoma, multiplies rapidly; creating Philadelphia chromosome of chronic myeloid leukemia. It a clone that produces large quantity of the antibodies. also inhibits c-kit and PDGF-R which are mutated in In 1975, Kohler and Milstein first fused lymphocytes to numerous solid tumors such as gastrointestinal stromal produce a cell line, which was both immortal and a producer tumors , lung cancer, prostate cancer, breast cancer, of specific antibodies. The two scientists were awarded the gliomas and seminoma. Nobel Prize for Medicine in 1984 for the development of this 2. Angiogenesis inhibitor includes bevacizumab, a vascular ‘hybridoma.’ The value of hybridomas to the field was not truly endothelial growth factor receptor inhibitor used in appreciated until about 1987, when MAbs were regularly treatment of metastatic colorectal cancer, metastatic renal produced in rodents for diagnostics. cell carcinoma, multiple myeloma and prostate cancer. Targeted therapies 3. Proteasome inhibitor: Proteasome is a structure inside the cell which breaks down proteins that have been labeled to Several classes of compounds included in targeted therapy undergo degradation and recycling. By binding part of the are as follows: proteasome, a drug can inhibit the breakdown of some of

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these proteins that have been marked for destruction. Table 1 Bortezomib, a proteasome inhibitor, is used in multiple myeloma patients on whom other therapies failed. Monoclonal antibodies approved in various indications 4. Biological response modifier: Denileukin is diftitox used in Drug Indications Year non- Hodgkin’s lymphoma. of approval 5 Monoclonal antibodies (MAbs): Some specific areas of MAbs uses are as follows: Abciximab (Reopro) Acute coronary syndrome 1994 1. Inhibition of allo-immune reactivity: In case of organ Basiliximab (Simulect) Organ transplantation 1998 transplantation, MAbs are used to provide Daclizumab (Zenapax) Organ transplantation 1997 Eculizumab Dermatomyositis, nephritis 2000 immunosupression by antagonism of IL-2 or by the Epratuzumab SLE 2005 elimination of activated T-cells. Infliximab (Remicade) Crohn’s disease, RA 1998 2. Inhibition of autoimmune reactivity: Infliximab is used Omalizumab (Xolair) Bronchial asthma 2004 in the treatment of Crohn’s disease and rheumatoid Muronomab (OKT3) Organ transplantation 1986 arthritis. Rituximab is also used in the treatment of Palivizumab Viral infection 1998 rheumatoid arthritis. 3. Antiplatelet activity: Coronary intervention in ischemic cardiac disease disrupts the intimal layer of the vessel antibody used, it could be chimeric antibodies or humanized and aggravates platelet aggregation, leading to antibodies. Another approach involves genetically engineered thrombosis. Glycoprotein IIb/IIIa receptor blocker is a mice that produce more human-like antibodies. clear target for MAbs, in the prevention and treatment Engineered MAbs have the advantages of decreased of this disease. immunogenicity, enhanced half-life and optimized specificity. 4. Infectious diseases: MAbs is being used for the treatment Some of the MAbs approved for various indications (except of respiratory syncytial virus (RSV) infection in cancers) are shown in Table 1. premature infants with bronchopulmonary disease. MAbs in cancer Several drugs are in the pipeline for the treatment of infective diseases. One possible treatment for cancer involves MAbs that bind 5. Cancer therapy: MAbs that bind cancer cell-specific only to cancer cell-specific antigen which induce an antigen induce an immunological response on the target immunological response in the target (cancer) cell. Such MAbs cell. Another strategy for antitumor therapy is to target could also .com).be modified to deliver toxins, radioisotopes, the receptors of growth factors like EGF and VEGF. cytokines or other active conjugates. It is also possible to design bispecific antibodies that can bind through their Fab regions MAbs of different origin to both the target antigen and to a conjugate or effecter cell. � Murine MAbs: are obtained from murine hybridomas In fact, every intact antibody can bind to cell receptors or other produced by fusion of B-lymphocytes from immunized proteins with its Fc region. mice or rats with murine myeloma cells. .medknowMost of the therapeutic antibodies act differently in cancer: � Chimeric antibodies: The antibody combines the 1. Induce lysis of cancer cells by altering host-immune antigen-binding parts (variable regions) of the mouse response,e.g. rituximab, alemtuzumab antibody with the effector parts (constant region) of a 2. Bind with extracellular domains of the receptors involved human antibody, e.g. infliximab, rituximab(www and in cell growth and proliferation, e.g. trastuzumab, abciximab. cetuximab, bevacizumab � : It combines only with the amino 3. Deliver radioisotopes to cancer cells: The antibodies are acids formingThis the antigen PDFa bindingsite is sitehosted available (the hyper variableby forMedknow freeconjugated download Publications to radioactive from substances to deliver regions), of a mouse (or rat) antibody part of the human radioactivity to cancer cells, e.g. tositumomab (conjugated antibody molecule, thus replacing its own hypervariable with I131, Ibritumomab [conjugated with Y90 and In111 ]) regions. Examples of humanized antibodies are 4. Deliver cytotoxic molecule: The antibody is conjugated to daclizumab, vitaxin, gemtuzumab ozogamicin, a cytotoxic molecule that kills the cancer cells, eg. trastuzumab and omalizumab. The advantage of human gemtuzumab, calicheamicin. MAbs is their potential to cause less immunogenic The MAbs that are available for the treatment of various reactions. cancers are shown in Table 2 and 3. Recombinant engineered MAbs MAbs for hematological malignancies Various approaches to overcome the problem of The treatment of hematological malignancies has been immunogenicity have been tried. One approach is to take the largely based on chemotherapy and radiotherapy. Although DNA that encodes the binding portion of monoclonal mouse improvement in response and survival rates has been seen antibodies and merge it with human antibody-producing DNA. over the years, poor response or relapses occur in a significant A mammalian cell culture is used to express DNA that produces proportion of patients. Moreover, conventional cytotoxic these half-mouse and half-human antibodies (bacteria cannot therapy is often associated with significant morbidity. be used for this purpose, since they cannot produce this kind Monoclonal antibodies have emerged as important therapeutic of glycoprotein). Depending on the size of the part of the mouse agents in a number of hematological malignancies.[1, 2] The main

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Table 2

Monoclonal antibodies for hematological malignancies

Drug Indication Dose Year of approval

Rituximab (Mabthera) B-cell lymphomas (anti-CD 20) 375 mg/m2 IV infusion weekly x 4 doses 1997 Gemtuzumab ozogamicin (Mylotarg) AML (anti-CD 33) 9 mg/m2 2 h infusion 2 doses 14 days apart 2000 Alemtuzumab (Campath) CLL (anti-CD 52) 30 mg, I.V., 3 times/week X 4-12 weeks 2001 Ibritumomab (Zevalin) NHL (anti-CD 20) 5.0 mCi, I.V., over 10 min 2002 Tositumomab (Bexxar) NHL (anti-CD 20) Day 0- 450 mg unlabeled infused over 1 h 2003 35 mg labeled (I 131) infused over 20 min Day 7-14 repeated similarly

Table 3

Monoclonal antibodies for nonhematological malignancies

Drug Indication Dose Year of approval

Bevacizumab (Avastin) Colorectal cancer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks 2004 Cetuximab (Erbitux) Colorectal cancer 400 mg/m2 , 2 h infusion followed by 250 mg/m2 weekly 2004 Trastuzumab (Herceptin) Breast Cancer 4 mg/kg, i.v., 90 min infusion followed by 2 mg/kg 30 min infusion weekly 1998

advantage of MAbs therapy compared to conventional The mechanism of action of rituximab is ADCC, CDC and chemotherapy is that the former specifically targets surface apoptosis .com). antigens that are uniquely expressed on tumor cells. Rituximab as single agent: In indolent lymphoma that has Since the introduction of rituximab as the first targeted progressed after prior chemotherapy, rituximab as a single MAb therapy for β-cell lymphoma relapse in December 1997, agent is associated with 50–60% response rates in the relapsed MAbs are extensively used in β-cell lymphoproliferative setting and 60%– 75% as front-line therapy. disorders.[3, 4] Rituximab in combination chemotherapy: Rituximab in vitro The application of MAbs, particularly directed at the CD33.medknow enhanced sensitivity to chemotherapy, thus creating a rationale and CD45 antigens, has been explored in acute myeloid for combined modality treatment.[7] The greatest synergy or leukemia with naked, radioimmune or antibody-chemotherapy additive effects were seen with the anthracycline, doxorubicin. conjugates. The radioimmunotherapy for non-Hodgkins Combination chemotherapy regimens with rituximab have been lymphoma (NHL), using two anti CD20 antibodies with(www different used in patients with low-grade lymphomas, like CHOP[8] CVP,[9] radioisotopes, have been approved for clinical use. The FC,[10] FCM[11] and FMD[12]. [Table 4] The R-CHOP regimen was antibodies for hematological malignancies directed at antigen associated with a response rate of 95%, including 58% targets including butThis not limited PDFa tosite CD30, is hosted CD5,available CD80 and by CD23 forMedknow freecomplete download responders. Publications In from a recent study, 428 patients with are at various stages of development. Indeed, some clinical untreated advanced-stage follicular lymphoma were randomly activity has been observed with CD30, CD80 and CD23 assigned for treatment with CHOP alone (n=205) or combined antibodies in Hodgkin’s disease, low grade NHL, and chronic with rituximab (R-CHOP; n=223). Treatment with R-CHOP lymphatic leukemia (CLL), respectively.[5] reduced the relative risk for treatment failure by 60% and Rituximab (anti CD20) and alemtuzumab (anti CD52) have significantly prolonged the time to treatment failure. Treatment proven efficacy in different clinical trials for the treatment of with R-CHOP resulted in a significantly higher overall response NHL[3] and CLL, respectively. rate of 96% compared to 90% for CHOP.[13] In a European trial, FCM plus rituximab was compared to FCM alone in previously Rituximab untreated follicular lymphoma or mantle cell lymphoma. In Rituximab is a chimeric humanized MAb that binds with the 43 subset patients with follicular lymphoma, combination CD20 molecule found on most β-cells and is used to treat therapy was associated with a response rate of 95% versus β-cell NHL. Rituximab has proven efficacy against a wide range 68% for FCM alone and a higher complete response rate as of β-cell malignancies, including follicular lymphoma, small well 36% Vs. 15%. A rituximab combined CVP regimen in lymphocytic lymphoma, marginal zone lymphoma, previously untreated low-grade lymphoma has shown a Waldenstrom’s macroglobulinemia, mantle cell lymphoma, response rate of 81%, with 50% complete response. diffuse large-cell lymphoma and post-transplant Rituximab has been added as part of sequential therapy lymphoproliferative disorders.[3, 4, 6] after chemotherapy, or as a consolidation treatment in patients

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Table 4 Table 5

Concurrent chemotherapy and rituximab in low-grade lymphoma Combination of gemtuzumab ozogamicin with cytotoxic chemo­ therapy[19] N Chemotherapy Response rate (%) Complete response (%) N Chemotherapy CR (%)

38 CHOP[8] 95 58 19 DAT NR 32 CVP[9] 81 50 55 DAT, DA, FLAG-Ida 85 39 FC[10] 97 74 18 DA 83 43 FCM[11] 95 - 57 MICE 54 134 FMD[12] 90 - 12 A 57

CVP - cyclophosphamide vincristine prednisone; CHOP - cyclophosphamide DAT - daunorubicin Ara-C thioguanine; DA - daunorubicin Ara-C; FLAG-ida ­ doxorubicin vincristine prednisone; FC - fludarabine cyclophosphamide; FCM ­ fludarabine ara-C G-CSF idarubicin; MICE - mitoxantrone cytarabine etoposide; fludarabine cyclophosphamide mitoxantrone; FMD - fludarabine mitoxantrone A - Ara-C, CR - Complete response. dexamethasone. who have already responded to chemotherapy. Rituximab was anticancer agents. Gemtuzumab ozogamicin is rapidly also used with biological-response modifiers in patients with internalized after binding to its target, followed by the release relapsed low-grade lymphoma. These include interferon alfa, of the potent antitumor calicheamicin derivative. This IL-2, IL-12 and GM-CSF. compound-induced double-stranded DNA breaks, resulting in apoptosis. It has been observed that within 3 to 6 h of infusion, Alemtuzumab a near-complete saturation of CD33 antigenic sites is reached [18] Alemtuzumab is a humanized antibody that reacts with for AML blasts, monocytes and granulocytes. It is approved the CD52 molecule that is found on both normal and malignant for the treatment of elderly patients (> 60 years) with CD33+ B- and T-lymphocytes, as well as NK-cells, monocytes, AML in first relapse and who are not considered candidates macrophages and tissues of the male reproductive system.[14] for cytotoxic chemotherapy. It was approved in May 2001 based on objective responses in Gemtuzumab ozogamicin as a single agent clearly serves patients with CLL that had relapsed after treatment with a role in the setting of relapsed AML. Several groups are fludarabine. Alemtuzumab was also evaluated in 50 patients evaluating targeted therapy in combination with cytotoxic .com). [19] with previously treated indolent lymphoma. Alemtuzumab, chemotherapy as a frontline therapy. [Table 5] when given with rituximab, has produced a response in 10 out Gemtuzumab has been used in combination with all-trans of 22 patients with CLL and it would be rational to use this retinoic acid (ATRA) in the treatment of acute promyelocytic [20] combination in low-grade lymphomas.[15] Alemtuzumab is the leukemia (APML) with favorable response. foundation of many eradication-based treatment approaches Radiolabeled anti-CD20 antibodies because of its ability to achieve clinical remissions and to successfully purge minimal residual disease (MRD) from both.medknow Radiolabeled antibodies such as yttrium 90-ibritumomab blood and bone marrow in B-CLL patients. The ability to clear tiuxetian (Y90), indium 111-ibritumomab (In111) and iodine 131­ MRD from bone marrow in patients achieving clinical complete tositumomab (I131) may be even more efficacious than MAbs response (CR) using alemtuzumab is a significant step(www forward in the treatment of NHL. In relapsed indolent lymphoma, in the treatment of B-CLL, and supports treatment strategies response rates of up to 80% have been noted with ibritumomab combining alemtuzumab with other agents. Purging of MRD tiuxetian (Y90), compared to 56% with rituximab.[21] from both blood andThis bone marrowPDF also is enablesavailable patients forfor freeTositumomab download and fromiIodine (I131) tositumomab is autologous hematopoietic stema cell site transplantation, hosted a strategyby Medknow administered Publications in two steps. The dosimetric step determines to achieve long-term remission.[16] individual patient pharmacokinetics, allowing a patient- specific Forty-one consecutive CLL patients underwent allogeneic dose to be calculated. This is followed by the therapeutic step, hematopoietic cell transplantation after conditioning with with administration of the therapeutic dose between 7 and 14 fludarabine, melphalan and alemtuzumab. The alemtuzumab­ days after the dosimetric dose.[22] based regimen was feasible and effective in patients with CLL Advanced-stage follicular β-cell lymphoma is considered with a relatively low rate of graft versus host disease . However, incurable. Anti CD20 radioimmunotherapy is effective in transplant related mortality remains relatively high as a result patients who have had a relapse after chemotherapy or who of a variety of viral and fungal infections. Studies are on to have refractory follicular lymphoma, but it has not been tested test the efficacy of reduced doses of alemtuzumab in this group in previously untreated patients. Seventy-six patients with of highly immunosuppressed patients.[17] stage III or IV follicular lymphoma received a single course of 131I-tositumomab as initial therapy.[23] This consisted of a Gemtuzumab ozogamicin dosimetric dose of tositumomab and 131I-labeled Gemtuzumab ozogamicin is a humanized MAb directed tositumomab followed one week later by a therapeutic dose, against CD33 linked to a calicheamicin derivative. This delivering 75 cGy of radiation to the total body. Ninety-five molecule is a member of the enediyne family of antitumor percent of the patients had overall response, and 75 percent antibiotics, which are more cytotoxic than other clinically used had a complete response. The use of polymerase chain reaction

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(PCR) to detect rearrangement of the BCL2 gene showed 2004 and the 2004 Gastrointestinal Cancers Symposium were molecular responses in 80 percent of assessable patients who reviewed and included as applicable. In a Phase III trial, had a complete clinical response. After a median follow-up of cetuximab was administered to 329 patients with colorectal 5.1 years, the actuarial 5-year progression-free survival for cancer who were irinotecan refractory and/or had failed to all patients was 59%, with a median progression-free survival respond to oxaliplatin treatment. Partial response was achieved of 6.1 years. Of the 57 patients who had a complete response, in 10.8% of patients who received cetuximab monotherapy and 40 remained in remission for 4.3 to 7.7 years. Hematologic 22.9% of patients who received cetuximab plus irinotecan toxicity was moderate, with no patient requiring transfusion therapy (P = 0.007). The overall response rate in two Phase II or hematopoietic growth factors. trials using the conventional dosing regimen of cetuximab to treat EGFR-expressing, metastatic colorectal cancer that was Monoclonal antibodies for nonhematological malig­ refractory to irinotecan therapy ranged from 9% to 12%. The nancies: drug was well tolerated with proper administration Targeted therapy against tumor-biological properties is an precautions. Unfortunately, the role of immunohistochemistry essential part of the individualized therapy concept in cancer. for EGFR expression continues to be a poor predictor of Next to risk-adapted strategies using conventional chemo- and/ patients who may benefit from cetuximab. Clinical studies of or endocrine therapies, antibody therapy has become an cetuximab in combination with radiation therapy and/or additional option. platinum in patients with squamous-cell head and neck cancer, as well as cetuximab in combination with various antineoplastic Trastuzumab agents for non-small cell lung cancer and pancreatic cancer The humanized MAb, trastuzumab (herceptin) is the first are going on. novel targeted therapy approved for routine clinical application Cetuximab has shown considerable activity both as in advanced breast cancer,[24] with HER2/ neu protein over monotherapy and in combination with chemotherapy in the expression as assessed by immunohistochemistry (IHC) and/ treatment of metastatic colorectal cancer that is resistant to or gene amplification as assessed by fluorescence in situ chemotherapy. The future of cetuximab lies in its use in hybridization (FISH) in their tumors responding well to combination with antineoplastic agents and/or radiation palliative trastuzumab therapy, either as single agent or in therapy in the treatment of colorectal cancer, head and neck combination with chemotherapy. New combinations with cancer, non-small cell lung cancer and pancreatic cancer. The endocrine therapy are currently being evaluated. Trastuzumab lack of a predictive marker that would allow clinicians to select is generally well tolerated. So far, considerable cardiotoxicity patients, who.com). are most lik ely to benefit from cetuximab therapy, was seen only in combination with doxorubicin. Thus, extensive especially taking into consideration the high costs of this cardio-monitoring is now performed in trials assessing further medication, remains a challenge. chemotherapeutic partners. Bevacizumab Clinical trials looking at early-trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) Bevacizumab is a recombinant human MAb that inhibits setting are still open for recruitment in Germany. Since only.medknow the biological activities of VEGF, a protein involved in the about 25 % of breast cancers, which are HER2/neu-positive, neovascularization of malignant tumors. Studies have shown are eligible for trastuzumab, novel targeted therapeutics for that bevacizumab has both cytostatic and cytotoxic effects, the remaining HER2/neu-negative tumors are needed. resulting in a reduction in tumor growth and increase in median Another therapeutic antibody, 2C4 (Pertuzumab,(www Omnitarg), survival time and time to tumor progression. Bevacizumab is is currently under clinical evaluation. It binds to a different available as an intravenous agent and carries FDA-approved epitope on HER2/neu than trastuzumab, and inhibits labeling for use in the first-line treatment of metastatic heterodimerization Thiswith other PDFa HERsite receptors.is hosted available Phase by I data forMedknow freecolorectal download cancer Publications (CRC) in fromcombination with fluorouracil-based showed that 2C4 is well tolerated and clinically active. chemotherapy. Bevacizumab has also yielded preliminary evidence of efficacy for breast, non-small-cell lung, pancreatic, Cetuximab prostate, renal and hepatic cancers, as well as for melanoma Cetuximab is a recombinant human/mouse chimeric and acute myelogenous leukemia.[26] Bevacizumab increases epidermal growth factor receptor (EGFR) MAb. It was approved survival when combined with irinotecan-based chemotherapy by the US FDA in February 2004 to be used in combination in first-line treatment of metastatic CRC. In a randomized phase with irinotecan for EGFR-expressing, metastatic colorectal II trial bevacizumab, 5-FU and leucovorin combination was cancer in patients who failed to improve with irinotecan-based compared with placebo plus FU/LV as first-line treatment in chemotherapy. Cetuximab was also approved for CRC.[27] Median survival was 16.6 months for the FU/LV/ administration as a single agent in the treatment of patients bevacizumab group and 12.9 months for FU/LV/placebo group. with EGFR-expressing, metastatic colorectal cancer who are Median progression-free survival in the two groups was 9.2 vs intolerant to irinotecan-based chemotherapy.[25] 5.5 months. The response rate was 26% in the bevacizumab A MEDLINE search[25] was conducted of articles published group and 15.2% in the FU/LV/placebo group. from 1976 to the present using the terms cetuximab, C225, In a phase II study, the response rate and overall survival IMC-C225, colon cancer, colorectal cancer, monoclonal therapy of pancreatic cancer patients who received gemcitabine with and target therapy. Abstracts presented at the American the recombinant humanized anti VEGF MAb bevacizumab was Society of Clinical Oncology annual meetings from 2000 to assessed. Fifty-two patients were enrolled at seven centers

394 Indian J Pharmacol | December 2006 | Vol 38 | Issue 6 | 390-396 Monoclonal antibodies between November 2001 and March 2004. All patients had rejection and infectious diseases and many products are being metastasis, and 83% had liver metastases. Eleven (21%) developed towards this end. patients had confirmed partial response and 24 (46%) had References stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 1. Multani PS, Grossbard ML. -based therapies for 5.4 months. The combination of bevacizumab plus gemcitabine hematological malignancies. J Clin Oncol 1998;16:3691-710. is active in advanced pancreatic-cancer patients. Additional 2. White CA, Weaver RL, Antonio J, Grillo- Lopez. Antibody- targeted immuno­ therapy for treatment of malignancy. Ann Rev Med 2001;52:125-45. study is warranted. A randomized phase III trial of gemcitabine 3. Kosmos C, Stamatopoulos K, Stavroyianni N, Savaris N and Papadaki T. Anti­ plus bevacizumab Vs. gemcitabine plus placebo is going on in CD20- based therapy of B cell lymphoma: state of the art. Leukemia 2002;16: pancreatic cancer and leukemia Group B.[28] 2004-5. In a recent study, the bevacizumab and erlotinib 4. Grillo-Lopez AJ, Hedrick E, Rashford M, Benyunes M. Rituximab: Ongoing combination was evaluated in the treatment of metastatic and future clinical development. Semin Oncol 2002;29:105-12. [29] 5. John CB. Monoclonal antibody therapy for hematologic malignancies: Intro­ clear-cell renal carcinoma, which was effective and well- duction. Semin Oncol 2003;30:421-3. tolerated. The efficacy of the combination suggests that 6. Montserrat E. Rituximab in chronic lymphocytic leukemia. Semin Oncol 2003;30: targeting of separate pathways critical to tumor growth and 34-9. dissemination may achieve results superior to either drug as 7. Dillman RO. Treatment of low grade B- cell lymphoma with the monoclonal a single agent. antibody rituximab. Semin Oncol 2003;30:434-47. In another study, bevacizumab in combination with 8. Czuczman MS, Grillo-Lpoz AJ, White CJ, Saleh M, Gordon L, LoBuglio, et al.Treatment of patients with low grade B- Cell Lymphoma with the combi­ capecitabine was assessed in breast cancer. Though there was nation of chimeric Anti-CD20 monoclonal antibody and CHOP Chemotherapy. a significant increase in response rate after addition of J Clin Oncol 1999;17:268-76. bevacizumab (19.8% Vs. 9.1%), this did not translate into 9. Garcia-Conde J, Conde E , Sierra J, Caballero D, Arranz R, Leon A, et al. improved progression-free survival and overall survival.[30] Rituximab (IDEC-C2B8) and CVP chemotherapy in follicular or low grade B- Panitumumab: Targets the epidermal growth factor cell lymphoma after relapse: Results after 6 months of follow up. Proc Am Soc Clin Oncol 2002;19:572. receptor (EGFR), which is over-expressed in lung, breast, 10. Sacchi S, Tucci Amerli F. Phase II study with fludarabine and cyclophospha­ bladder, pancreatic, colorectal, kidney and head and neck mide plus rituximab in relapsed follicular lymphoma patients. Blood 2002; cancers. Research has demonstrated that cancer cells can 100:572. become dependent on growth signals mediated through EGFr 11. Hiddeman W, Forstpointer R, Fiedler F. The addition of rituximab to combina­ for their survival. In preclinical research, panitumumab tion chemotherapy with fludarabine, cyclophosphamide, mitoxantrone(FCM) results in a significant.com). increase of overall response as compared to FCM alone monotherapy has been shown to inhibit the growth of human in patients with relapsed or refractory follicular and mantle cell lymphoma. [31] tumors in mice. Panitumumab is being evaluated in a Blood 2001;98:844. comprehensive clinical program for several indications. The 12. Cabanillas F, McLaughlin P, Hagemeister FB. Molecular responses with FMD program currently includes clinical trials to evaluate plus rituximab chemoimmunotherapy for stage IV indolent follicular non­ panitumumab in renal, colorectal and non-small cell lung Hodgkins lymphoma. Blood 2000;96:331. cancers. 13. Hiddeman W, Kneba M, Dreyling M, Schmitz N, Lengfedler E, Schmits R, et al. Frontline therapy with rituximab added to the combination of CHOP signifi- Mitumumab: Mitumumab is indicated in the treatment of.medknow cantly improves the outcome for patients with advanced stage follicular lym- SCLC, Melanoma and soft tissue sarcoma (CD11a).[32] phoma compared with therapy with CHOP alone: results of a prospective LymphoCid- Epratuzumab is a MAb that targets CD22 protein randomized study of the German Low –Grade Lymphoma Study Group . Blood found on β-cells. It has been tested in people with high- and 2005;106:3725-32. low-grade NHL that has come back or is proving(www difficult to 14. Dyer MJ. The role of Campath-1 antibodies in the treatment of lymphoid ma- lignancies Semin Oncol 1999;26:52-7. treat. It has been tested on its own and in combination with 15. Faderl S, Thomas DA, O’Brien S. An exploratory study of the combination of rituximab. monoclonal antibodies Campath- IH and rituximab in the treatment of CD-52 Pertuzumab: ThisThis is a recombinant PDFa site is humanized hosted available monoclonal by forMedknow freeand downloadCD20 positivePublications chronic lymphoidfrom disorders. Blood 2001;98:365. antibody (2C4) that binds to the extracellular domain II of the 16. Montillo M, Schinkoethe T, Etler T. Eradication of minimal residual disease HER-2 receptor and blocks its ability to dimerize with other with alemtuzumab in B-CLL patients:The need for a standard method of de­ tection and the potential impact of bone marrow clearance on disease out­ HER receptors. It represents a new class of targeted come. Cancer Invest 2005;23:488-96. therapeutics known as HER dimerization inhibitors. A recent 17. Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G, et al. Results Phase I study[33] in patients with advanced breast cancer has of alemtuzumab – based reduced intensity allogenic transplantation for chronic shown that it is well tolerated and is clinically active, suggesting lymphocytic leukemia: a British Society of Blood and Marrow Transplantation that inhibition of dimerisation may be an effective anticancer Study. Blood 2006;107:1724-30. strategy. 18. van Der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, et al. Targeting of the CD33-calcheamicin immunoconjugate Conclusion Mylotarg (CMA-676) in acute myeloid leukemia: In vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 2001;97: After 30 years of development, therapy with MAbs has been 3197-204. recognized as a promising therapeutic tool. Its clinical use is 19. Tomblyn MR, Tallman MS. New developments in antibody therapy for AML. most widespread in the field of oncology, where half of the Semin Oncol 2003;30:502-8. agents approved for routine clinical use are employed and a 20. Estey EH, Giles FJ, Beran M, O’Brien S, Pierce S A, Stefan H, et al. Experi­ ence with gemtuzumab ozogamicin and all-trans retinoic acid in untreated acute large number of molecules are currently undergoing clinical promyelocytic leukemia. Blood 2002;99:4222-4. trials. Monoclonal antibodies using human genes herald a new 21. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmaanouilides C, Joyce era in the treatment of cancer, autoimmune disease, graft R, et al. Randomized controlled trial of yttrium 90 labeled ibritumomab tiuxetan

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radioimmunotherapy versus rituximab immunotherapy for patients with relapsed cancer: Results of a randomized phase II trial. J Clin Oncol 2005;23:3697-705. or refractory low grade, follicular or transformed B-cell non-Hodgkins lymphoma. 28. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase J Clin Oncol 2002;20:2453-63. II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic 22. Davies AJ. A review of tositumomab and I131 tositumomab radioimmunotherapy cancer. J Clin Oncol 2005;23:8033-40. for the treatment of follicular lymphoma. Expert Opin Biol Ther 2005;5:577-88. 29. Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughmann C, Greco A. 23. Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, et al. 131 I­ Treatment of metastatic renal carcinoma with a combination of bevacizumab tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med and erlotinib. J Clin Oncol 2005;23:7889-96. 2005;352:441-9. 30. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab 24. Dillman RO. Perceptions of Herceptin: A monoclonal antibody for treatment of plus capecitabine in patients with previously treated metastatic breast cancer. breast cancer. Cancer Biother Radiopharm 1999;14:5-10. J Clin Oncol 2005;23:792-9. 25. Wong SF. Cetuximab: An epidermal growth factor receptor monoclonal anti­ 31. Vectibix Package Insert Amgen USA body for the treatment of colorectal cancer. Clin Ther 2005;27:684-94. 32. Werner RG. The development and production of biopharmaceuticals. 26. Motl S. Bevacizumab in combination chemotherapy for colorectal and other Bioprocess International 2005;3:9. cancers. A J Health Sys Pharm 2005;62:1021-32. 33. Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mandelson BS, et al. 27. Kabbinaver FF, Schulz J, McCleod M, Patel T, Hamm John T, Hecht R, et al. Addition Phase I clinical study of pertuzumab, a novel Her dimerization inhibitor. In of bevacizumab to bolus flurouracil and leucovorin in first line metastatic colorectal patients with advanced cancer. J Clin oncol 2005;23:2534-43.

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