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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) CD20 monoclonal antibody therapy for B-cell lymphona van der Kolk, L.E. Publication date 2001 Link to publication Citation for published version (APA): van der Kolk, L. E. (2001). CD20 monoclonal antibody therapy for B-cell lymphona. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:29 Sep 2021 CC h a p t e Introductionn and outline of the thesis Introductionn and outline of the thesis Introduction n Low-gradee non-Hodgkin's lymphoma (NHL) Non-Hodgkin'ss lymphomas are a heterogeneous group of malignancies of mature lymphoid cells.. Over 90% of the non-Hodgkin's lymphomas is of B-cell origin. The clinical course variess from indolent to highly aggressive. Over the past decades, several lymphoma classificationss have been developed and used in different parts of the world.1 The Kiel classification2,, introduced in 1974, relates the different lymphomas to the differentiation stagess of normal T- and B-cells, i.e. to their 'normal counterpart'. It is based on morphology andd immunophenotypical analysis of lymphoma cells. In the 'Working Formulation'3, lymphomass have been subdivided into low-, intermediate-, and high-risk lymphomas, dependentt on their clinical behavior. This classification was based on the analysis of the clinicall data of a large group of lymphoma patients treated in the 1970's. The Working Tablee 1. Comparison of Working Formulation and REAL classification with respect to B-lineage lymphomas s Workingg formulation REALL classifcation A** Small lymphocytic lymphoma consistent with CLL B-celll chronic lymphocytic leukemia Lymphoplasmacytoidlymphoma/immunocytoma a Smalll lymphocytic lymphoma B-celll prolymphocyte leukemia Smalll lymphocytic, plasmacytoid lymphoma Lymphoplasmacytoidd lymphoma Smalll lymphocytic lymphoma Extranodall marginal zone B-cel! lymphoma Smalll lymphocytic lymphoma Nodall marginal zone B-cell lymphoma Smalll lymphocytic lymphoma Splenicc marginal zone B-cell lymphoma Hairyy cell leukemia Plasmacytoma a Plasmacytoma/Myeloma a BB Follicular, predominantly small cleaved cell Folliclee center lymphoma, follicular grade I CC Follicular, mixed small cleaved and large cell Folliclee center lymphoma, follicular grade II DD Follicular, predominantly large cell Folliclee center lymphoma, follicular grade III EE Diffuse lymphoma, small cleaved cell Folliclee center lymphoma, diffuse small cell Mantlee cell lymphoma FF Diffuse, mixed small and large cell Folliclee center lymphoma, diffuse small cell GG Diffuse, large cell lymphoma Diffusee large B-cell lymphoma HH Diffuse large cell immunoblastic lymphoma Diffusee large B-cell lymphoma II Lymphoblastic lymphoma B-precursorr lymphoblastic lymphoma JJ Small non-cleaved, Burkitt's lymphoma Burkitt'ss lymphoma Smalll non-cleaved, non-Burkitt's lymphoma Highh grade B-cell lymphoma, Burkitt-like Workingg Formulation A-C: low-grade non-Hodgkin's lymphomas; D-G: intermediate-grade NHL; H-J: high-gradee NHL 9 9 Chapterr 1 formulationn and Kiel classification have been used predominantly in the United States and Europee respectively. However, in order to be able to compare scientific data (e.g. on treatment results),, one lymphoma classification is definitely required. Therefore, the Revised European- Americann lymphoma classification (REAL) was presented by hematologists and pathologists fromm Europe, the Unites States and Asia in 1994 (table 1).4 This classification not only uses morphologyy and immunophenotyping, but also incorporates cytogenetic, molecular and clinicall data in order to categorize the different lymphomas. Recently, the 'World Health Organizationn Classification of hematologic malignancies' was introduced.5 This classification closelyy resembles the REAL classification with respect to the non-Hodgkin's lymphomas. Low-gradee lymphomas are characterized by an indolent clinical course, with a median survival off 8-10 years after diagnosis. Management of low-grade NHL varies from wait-and-see to single-agentt or aggressive combination chemotherapy. Although 60-90% of patients achievess a remission after initial treatment, all patients eventually relapse. Both response ratee and response duration to subsequent therapies decline, indicating an increasing chemoresistancee of the lymphoma.6 Unfortunately, over the past decades overall survival hass not significantly been altered by therapy, and curation has not been described.67 Antibodyy based immunotherapy Althoughh there are many different forms of immunotherapy (table 2), at present only monoclonall antibody(mAb)-based therapies have reached the stage of extensive clinical Tablee 2. Treatment modalities in immunotherapy Passive e tumorr specific monoclonall antibodies (mAbs) unconjugatedd mAbs radiolabeledd mAbs toxin-conjugatedd mAbs cytokine/chemokine-conjugatedd mAbs drug/enzyme-conjugatedd mAbs bispeciff ic mAbs tumorspecificc T-cells nonn specific LAKK cells cytokines s anti-cytokinemAbs s Active e tumorspecific c vaccinationn using tumorr cells proteins// peptides ( DC) DNA A nonn specific Bacilluss Calmette-Guerin (BCG) Corynee bacterium Parvum Abbreviation:: LAK cells: lymphokine-activated killer cells; DC= dendritic cells 10 0 Introductionn and outline of the thesis testing.. Theoretically, mAb-based therapy offers an attractive approach for the treatment off malignancies. By targeting tumor-specific antigens, antibody-based therapy is expected too confer less non-specific toxicity than chemotherapy. Moreover, since mAbs might use distinctt cytotoxic mechanisms, chemoresistance of tumor cells may be overcome.8 Thee clinical efficacy of unconjugated mAbs is dependent on certain critical characteristics off both the target antigen and the mAb itself. First, the target antigen should be tumor- specific,, present on all tumor cells in sufficient density and it should not be expressed on otherr tissues. For optimal interaction between antigen and antibody, the affinity of the antibodyy for the antigen is also of importance. Furthermore, upon ligation, the target antigen shouldd not internalize or be shed, resulting in antigen-negative tumor cells. In case of shedding,, soluble antigen may hamper interaction of the mAbs with the target cells.9;10 Withh respect to the mAb itself, certain problems may limit its efficacy (table 3). First, since mAbss are large proteins, kinetics of tissue distribution of mAbs are slow when compared to smalll molecules and penetration into large tumors, which are often poorly vasculated, might bee suboptimal. Furthermore, tissue distribution may not be uniform. F(ab')2 fragments, F(ab') fragmentss or single-chain Fv constructs are smaller proteins and therefore may have a better tissuee penetration. However, shorter half-life and lower in vivo stability are limitations that maymay impede clinical efficacy of these smaller constructs.1113 Second, antibodies may be immunogenic,, leading to the formation of antibodies resulting in neutralization and/or Tablee 3. Potential obstacles to monoclonal antibodybased therapies 11 non-specific binding of the mAb to normal tissues 22 low antigen density on tumor cells/induction/presence of antigen-negative tumor cells 33 low affinity of mAb for antigen 44 antigen modulation (shedding/internalization) 55 poor penetration of mAbs into (bulky) tumors 66 induction of anti-mAb antibodies 77 inability of the mAb to activate host effector mechanisms/resistance of tumor cells to cytotoxic mechanismss of the mAb clearancee of the therapeutic antibody. This problem was first identified in initial clinical trials withh murine antibodies, in which human anti-mouse antibodies were formed rapidly in a considerablee proportion of patients (~ 25%).1415 Finally, the efficacy of the murine antibodies mayy be limited due to the variable ability of different murine Fc-tails to interact with human effectorr mechanisms. These latter two problems can be overcome by using chimeric antibodies,, in which the variable region of the murine antibody is coupled to a human Fc- tail.. Chimeric antibodies are less immunogenic, have a longer half-life and are more efficient; inn mediating Fc-dependent functions.16"18 11 1 Chapterr 1 Anti-tumorr mechanisms of unconjugated mAbs include direct mechanisms like the induction off apoptosis or a growth arrest, and indirect mechanisms, i.e. complement-dependent cytotoxicityy (CDC) and antibody-dependent cellular cytotoxicity (ADCC).18;19 Inn addition to unconjugated antibodies, conjugated antibodies are already used clinically. Antibodiess may be conjugated to radioactive isotopes, such as 131 iodine <1311) or 90 yttrium ("Y),, or to toxic conjugates from plant or bacterial origin, such as ricin, diphtheria toxin
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