Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

mAbs

Volumn 5, Issue 6, 2013, Pages 826-837

  Golay, Josée ^a   Semenzato, Gianpietro ^b   Rambaldi, Alessandro ^a   Foà, Robin ^c   Gaidano, Gianluca ^d   Gamba, Enrica ^e   Pane, Fabrizio ^f   Pinto, Antonello ^g   Specchia, Giorgina ^h   Zaja, Francesco ⁱ   Regazzi, Mario ^j  

^a PAPA GIOVANNI XXIII HOSPITAL   (Italy)

^b UNIVERSITY OF PADUA MEDICAL SCHOOL   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

^d Amedeo Avogadro University   (Italy)

^e Roche Diagnostics Systems SpA   (Italy)

^f UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^g NATIONAL CANCER INSTITUTE   (Italy)

^h UNIVERSITY OF BARI   (Italy)

ⁱ DISM   (Italy)

^j FONDAZIONE IRCCS POLICLINICO SAN MATTEO   (Italy)

more..

Author keywords

B NHL; CLL; FcRn; Fc Rs; Pharmacodynamics; Pharmacokinetics; Rituximab

Indexed keywords

COMPLEMENT; DOXORUBICIN; FC RECEPTOR; HUMAX CD 20; IMMUNOGLOBULIN G1 ANTIBODY; METHOTREXATE; OBINUTUZUMAB; OFATUMUMAB; PREDNISONE; RITUXIMAB; TRASTUZUMAB; UNCLASSIFIED DRUG; VINCRISTINE; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY; PROTEIN BINDING;

ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTIGEN BINDING; AREA UNDER THE CURVE; BINDING AFFINITY; CANCER CHEMOTHERAPY; CHRONIC LYMPHATIC LEUKEMIA; CYTOTOXIC T LYMPHOCYTE; DRUG ABSORPTION; DRUG ACCUMULATION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG EXPOSURE; DRUG HALF LIFE; DRUG MECHANISM; GLYCOSYLATION; HUMAN; KUPFFER CELL; LARGE CELL LYMPHOMA; MAINTENANCE THERAPY; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NATURAL KILLER CELL; PHAGOCYTOSIS; PHARMACODYNAMICS; PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA; PROTEIN DEGRADATION; REVIEW; TREATMENT RESPONSE; TUMOR VOLUME; BIOLOGICAL MODEL; NEOPLASMS; SEX DIFFERENCE;

ANTIBODIES, MONOCLONAL, MURINE-DERIVED; ANTINEOPLASTIC AGENTS; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; PROTEIN BINDING; SEX FACTORS;

EID: 84889798743     PISSN: 19420862     EISSN: 19420870     Source Type: Journal    
DOI: 10.4161/mabs.26008     Document Type: Review

References (105)

1. Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol 2000; 27(Suppl 12):17-24; PMID:11225995
2. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 1994; 15:450-4; PMID:7524522; http://dx.doi.org/10. 1016/0167-5699(94)90276-3
3. Kehrl JH, Riva A, Wilson GL, Thévenin C. Molecular mechanisms regulating CD19, CD20 and CD22 gene expression. Immunol Today 1994; 15:432-6; PMID:7524520; http://dx.doi.org/10.1016/0167-5699(94)90273-9
4. Martin P, Furman RR, Coleman M, Leonard JP. Phase I to III trials of anti-B cell therapy in non-Hodgkin's lymphoma. Clin Cancer Res 2007; 13:5636s-42s; PMID:17875800; http://dx.doi.org/10.1158/1078-0432.CCR-07-1085
5. St Clair EW. Novel targeted therapies for autoimmunity. Curr Opin Immunol 2009; 21:648-57; PMID:19828300; http://dx.doi.org/10.1016/j.coi.2009.09.008
6. Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010; 47:115-23; PMID:20350658; http://dx.doi.org/10.1053/j.seminhema tol.2010.01.011
7. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M. Biologic response of B lymphoma cells to anti- CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000; 95:3900-8; PMID:10845926
8. Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, Botto M, Introna M, Golay J. Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 2003; 171:1581-7; PMID:12874252
9. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002; 99:754-8; PMID:11806974; http://dx.doi.org/10.1182/blood.V99.3.754
10. Bologna L, Gotti E, Da Roit F, Intermesoli T, Rambaldi A, Introna M, Golay J. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. J Immunol 2013; 190:231-9; PMID:23225880; http://dx.doi.org/10.4049/jimmunol. 1202645
11. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 2004; 104:2635-42; PMID:15226177; http://dx.doi.org/10.1182/blood-2004-03-1110
12. Leidi M, Gotti E, Bologna L, Miranda E, Rimoldi M, Sica A, Roncalli M, Palumbo GA, Introna M, Golay J. M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro. J Immunol 2009; 182:4415-22; PMID:19299742; http://dx.doi.org/10.4049/jimmunol.0713732
13. Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, Tedder TF. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 2004; 199:1659- 69; PMID:15210744; http://dx.doi.org/10.1084/jem.20040119
14. Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology 2002; 107:176-82; PMID:12383196; http://dx.doi. org/10.1046/j.1365-2567.2002.01495.x
15. Ivanov A, Beers SA, Walshe CA, Honeychurch J, Alduaij W, Cox KL, Potter KN, Murray S, Chan CH, Klymenko T, et al. Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells. J Clin Invest 2009; 119:2143-59; PMID:19620786
16. Alduaij W, Ivanov A, Honeychurch J, Cheadle EJ, Potluri S, Lim SH, Shimada K, Chan CH, Tutt A, Beers SA, et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 2011; 117:4519-29; PMID:21378274; http://dx.doi.org/10.1182/blood-2010-07-296913
17. Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 2010; 115:4393-402; PMID:20194898; http://dx.doi.org/10. 1182/blood-2009-06-225979
18. Abès R, Gélizé E, Fridman WH, Teillaud JL. Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. Blood 2010; 116:926-34; PMID:20439625; http://dx.doi. org/10.1182/blood-2009-10-248609
19. Boross P, Leusen JH. Mechanisms of action of CD20 antibodies. Am J Cancer Res 2012; 2:676-90; PMID:23226614
20. Bologna L, Gotti E, Manganini M, Rambaldi A, Intermesoli T, Introna M, Golay J. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immunol 2011; 186:3762-9; PMID:21296976; http://dx.doi.org/10.4049/jimmunol.1000303
21. Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French RR, van Meerten T, Ebeling S, Vink T, Slootstra JW, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006; 177:362- 71; PMID:16785532
22. Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol 2012; 5:64; PMID:23057966; http://dx.doi.org/10.1186/1756-8722-5-64
23. Beers SA, Chan CH, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol 2010; 47:107- 14; PMID:20350657; http://dx.doi.org/10.1053/j.seminhematol.2010.01.001
24. Golay J, Bologna L, André PA, Buchegger F, Mach JP, Boumsell L, Introna M. Possible misinterpretation of the mode of action of therapeutic antibodies in vitro: homotypic adhesion and flow cytometry result in artefactual direct cell death. Blood 2010; 116:3372-3, author reply 3373-4; PMID:21030571; http://dx.doi.org/10.1182/blood-2010-06-289736
25. Klein C, Lammens A, Schäfer W, Georges G, Schwaiger M, Mössner E, Hopfner KP, Umaña P, Niederfellner G. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs 2013; 5:22-33; PMID:23211638; http:// dx.doi.org/10.4161/mabs. 22771
26. Bruhns P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012; 119:5640-9; PMID:22535666; http://dx.doi.org/10.1182/blood-2012-01-380121
27. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008; 8:34-47; PMID:18064051; http://dx.doi.org/10. 1038/nri2206
28. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715- 25; PMID:17703228; http://dx.doi.org/10.1038/nri2155
29. Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs 2011; 3:422-30; PMID:22048693; http://dx.doi.org/10.4161/mabs.3.5.16983
30. Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, Iyer S, DeForge LE, Theil FP, Fielder PJ, Prabhu S. Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice. MAbs 2012; 4:101-9; PMID:22327433; http://dx.doi.org/10.4161/mabs.4.1.18543
31. Idusogie EE, Presta LG, Gazzano-Santoro H, Totpal K, Wong PY, Ultsch M, Meng YG, Mulkerrin MG. Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol 2000; 164:4178-84; PMID:10754313
32. Idusogie EE, Wong PY, Presta LG, Gazzano-Santoro H, Totpal K, Ultsch M, Mulkerrin MG. Engineered antibodies with increased activity to recruit complement. J Immunol 2001; 166:2571-5; PMID:11160318
33. Michaelsen TE, Sandlie I, Bratlie DB, Sandin RH, Ihle O. Structural difference in the complement activation site of human IgG1 and IgG3. Scand J Immunol 2009; 70:553-64; PMID:19906198; http://dx.doi.org/10.1111/j.1365-3083. 2009.02338.x
34. Pawluczkowycz AW, Beurskens FJ, Beum PV, Lindorfer MA, van de Winkel JG, Parren PW, Taylor RP. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti- CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 2009; 183:749-58; PMID:19535640; http://dx.doi.org/10.4049/ jimmunol.0900632
35. Jefferis R. Isotype and glycoform selection for antibody therapeutics. Arch Biochem Biophys 2012; 526:159- 66; PMID:22465822; http://dx.doi.org/10. 1016/j.abb.2012.03.021
36. Schneider CK, Vleminckx C, Gravanis I, Ehmann F, Trouvin JH, Weise M, Thirstrup S. Setting the stage for biosimilar monoclonal antibodies. Nat Biotechnol 2012; 30:1179-85; PMID:23222783; http://dx.doi.org/10.1038/nbt.2447
37. Ferrara C, Brünker P, Suter T, Moser S, Püntener U, Umaña P. Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous beta1, 4-N-acetylglucosaminyltransferase III and Golgi alpha-mannosidase II. Biotechnol Bioeng 2006; 93:851-61; PMID:16435400; http://dx.doi.org/10.1002/bit.20777
38. Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci 2009; 30:356-62; PMID:19552968; http://dx.doi.org/10.1016/j.tips.2009.04.007
39. Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima-Miyama K, Kuni-Kamochi R, Nakano R, Yano K, Kakita S, et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 2007; 17:104-18; PMID:17012310; http://dx.doi.org/10.1093/glycob/ cwl057
40. Cérutti M, Golay J. Lepidopteran cells, an alternative for the production of recombinant antibodies? MAbs 2012; 4:294-309; PMID:22531440; http://dx.doi.org/10.4161/mabs.19942
41. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence- Bruckler I, White CA, Cabanillas F, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16:2825-33; PMID:9704735
42. Harjunpää A, Wiklund T, Collan J, Janes R, Rosenberg J, Lee D, Grillo-López A, Meri S. Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma. Leuk Lymphoma 2001; 42:731-8; PMID:11697503; http://dx.doi.org/10.3109/ 10428190109099335
43. Lampson LA. Monoclonal antibodies in neuro-oncology: Getting past the blood-brain barrier. MAbs 2011; 3:153-60; PMID:21150307; http://dx.doi.org/10. 4161/mabs.3.2.14239
44. Pels H, Schulz H, Manzke O, Hom E, Thall A, Engert A. Intraventricular and intravenous treatment of a patient with refractory primary CNS lymphoma using rituximab. J Neurooncol 2002; 59:213-6; PMID:12241117; http://dx.doi.org/10.1023/A:1019999830455
45. Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, Batchelor T, Krouwer H, Hwang J, Auerback G, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood 2013; 121:745-51; PMID:23197589; http://dx.doi.org/10.1182/blood-2012-07-440974
46. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Taylor AF, Rohane P. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001; 108:E36; PMID:11483846; http://dx.doi.org/10. 1542/peds.108.2.e36
47. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368:2455- 66; PMID:23688323; http://dx.doi.org/10.1056/NEJMoa1304048
48. Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, et al.; GO-FORWARD Study. Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009; 68:789-96; PMID:19066176; http://dx.doi.org/10.1136/ard.2008.099010
49. Salar A, Avivi I, Larouche JF, Janikova A, Pereira J, Brewster M, Catalani O, McIntyre C, Sayyed P, Haynes A. Final results of the BP22333 Study demonstrate Non-inferior pharmacokinetics (PK) and safety of subcutaneous (SC) administration of rituximab compared to intravenous (IV) administration as maintenance therapy in patients with follicular lymphoma (FL). Blood 2012; 120:1641a
50. Assouline S, Buccheri V, Delmer A, Doelken G, Gaidano G, McIntyre C, Brewster M, Hourcade-Potelleret F, Sayyed P, Badoux X. Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL: Initial results of a phase Ib study (SAWYER- BO25341) show non-inferior pharmacokinetics and comparable safety to that of intravenous rituximab. Blood 2012; 120:1637a
51. Davies A, Merli F, Mihaljevik B, Siritanaratkul N, Solal-Celigny P, Boehnke A, Berge C, McIntyre C, Barrett M, Macdonald D. Pharmacokinetics (PK), safety and overall response rate (ORR) achieved with subcutaneous /SC) administration of rituximab in combination with chemotherapy were comparable to those achieved with intravenous (IV) administration in patients (pts) with follicular lymphoma (FL) in the first-line setting: Stage 1 results of the Phase III SABRINA study (BO22334). Blood 2012; 120:1629a
52. Regazzi MB, Iacona I, Avanzini MA, Arcaini L, Merlini G, Perfetti V, Zaja F, Montagna M, Morra E, Lazzarino M. Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit 2005; 27:785- 92; PMID:16306856; http://dx.doi.org/10. 1097/01.ftd.0000184162.60197.c1
53. Dostalek M, Gardner I, Gurbaxani BM, Rose RH, Chetty M. Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet 2013; 52:83-124; PMID:23299465; http://dx.doi.org/10.1007/s40262-012-0027-4
54. Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood 2012; 119:5126-32; PMID:22431570; http://dx.doi.org/10.1182/blood-2012-01-404368
55. Sehn LH, Assouline SE, Stewart DA, Mangel J, Gascoyne RD, Fine G, Frances-Lasserre S, Carlile DJ, Crump M. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood 2012; 119:5118-25; PMID:22438256; http://dx.doi.org/10.1182/blood-2012-02-408773
56. Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K, Link BK, Pinter-Brown L, Radford J, Hellmann A, et al.; 405 Study Investigators. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 2012; 119:3698-704; PMID:22389254; http://dx.doi.org/10.1182/blood-2011-09-378323
57. Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies- -mechanistic modeling applied to drug development. Curr Opin Drug Discov Devel 2007; 10:84-96; PMID:17265746
58. Salar A, Bouabdallah R. MaIntyre C, Sauyyed P, Bittner B. A two stage phase Ib study to investigate the pharmacokinetics, safety and tolerability of subcutaneous rituximab in patients with follicular lymphoma as part of maintenance treatment. Blood 2010; 116:2858a
59. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2008; 84:548-58; PMID:18784655; http://dx.doi.org/10.1038/clpt.2008.170
60. Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm Res 2012; 29:490-9; PMID:21887597; http://dx.doi.org/10.1007/s11095-011-0578-3
61. McLennan DN, Porter CJ, Edwards GA, Martin SW, Heatherington AC, Charman SA. Lymphatic absorption is the primary contributor to the systemic availability of epoetin Alfa following subcutaneous administration to sheep. J Pharmacol Exp Ther 2005; 313:345-51; PMID:15579493; http://dx.doi.org/10.1124/jpet.104.078790
62. Keating GM. Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma. Drugs 2010; 70:1445-76; PMID:20614951; http://dx.doi.org/10.2165/11201110- 000000000-00000
63. Muller PY, Brennan FR. Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther 2009; 85:247-58; PMID:19177065; http://dx.doi.org/10.1038/clpt. 2008.273
64. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004; 93:2645-68; PMID:15389672; http://dx.doi.org/10.1002/jps.20178
65. de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 2005; 44:1135-64; PMID:16231966; http://dx.doi.org/10.2165/00003088-200544110-00003
66. Müller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynalova S, Wenger M, Nickenig C, Peter N, Lengfelder E, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 2012; 119:3276- 84; PMID:22337718; http://dx.doi.org/10.1182/blood- 2011-09-380949
67. Beum PV, Peek EM, Lindorfer MA, Beurskens FJ, Engelberts PJ, Parren PW, van de Winkel JG, Taylor RP. Loss of CD20 and bound CD20 antibody from opsonized B cells occurs more rapidly because of trogocytosis mediated by Fc receptor-expressing effector cells than direct internalization by the B cells. J Immunol 2011; 187:3438-47; PMID:21841127; http://dx.doi.org/10.4049/jimmunol. 1101189
68. Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, Mangat R, Joshi A, Visich J. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol 2012; 52:1918-26; PMID:22235140; http://dx.doi.org/10.1177/0091270011430506
69. Rahman A, Carmichael D, Harris M, Roh JK. Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Res 1986; 46:2295-9; PMID:3697976
70. Nelson RL, Dyke RW, Root MA. Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer. Cancer Treat Rev 1980; 7(Suppl 1):17-24; PMID:7438117; http://dx.doi.org/10.1016/S0305-7372(80)80003-X
71. Harrold JM, Straubinger RM, Mager DE. Combinatorial chemotherapeutic efficacy in non- Hodgkin lymphoma can be predicted by a signaling model of CD20 pharmacodynamics. Cancer Res 2012; 72:1632-41; PMID:22350416; http://dx.doi.org/10.1158/0008-5472.CAN-11-2432
72. Yin A, Li J, Hurst D, Visich J. Population pharmacokinetics (PK) and association of PK and clinical outcomes of rituximab in patients with non-Hodgkin's lymphoma. J Clin Oncol 2010; 28(suppl 15):e13108
73. Berinstein NL, Grillo-López AJ, White CA, Bence- Bruckler I, Maloney D, Czuczman M, Green D, Rosenberg J, McLaughlin P, Shen D. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 1998; 9:995-1001; PMID:9818074; http://dx.doi.org/10.1023/A:1008416911099
74. Jäger U, Fridrik M, Zeitlinger M, Heintel D, Hopfinger G, Burgstaller S, Mannhalter C, Oberaigner W, Porpaczy E, Skrabs C, et al.; Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) Investigators. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica 2012; 97:1431-8; PMID:22511498; http://dx.doi.org/10.3324/ haematol.2011.059246
75. Gordan LN, Grow WB, Pusateri A, Douglas V, Mendenhall NP, Lynch JW. Phase II trial of individualized rituximab dosing for patients with CD20- positive lymphoproliferative disorders. J Clin Oncol 2005; 23:1096-102; PMID:15657402; http://dx.doi.org/10.1200/JCO.2005.12.171
76. Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012; 30:4462- 9; PMID:23091101; http://dx.doi.org/10.1200/JCO.2012.41.9416
77. Carella AM, de Souza CA, Luminari S, Marcheselli L, Chiappella A, di Rocco A, Cesaretti M, Rossi A, Rigacci L, Gaidano G, et al. Prognostic role of gender in diffuse large B-cell lymphoma treated with rituximab containing regimens: a Fondazione Italiana Linfomi/ Grupo de Estudos em Moléstias Onco-Hematológicas retrospective study. Leuk Lymphoma 2013; 54:53-7; PMID:22712840; http://dx.doi.org/10.3109/10428194.2012.691482
78. Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti- TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012; 91:635-46; PMID:22357456; http://dx.doi.org/10.1038/clpt.2011.328
79. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, et al.; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104:634-41; PMID:15016643; http://dx.doi.org/10.1182/blood-2003-06-2095
80. Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 2013; 381:1817-26; PMID:23615461; http://dx.doi.org/10.1016/S0140-6736(13)60313-X
81. Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 2013; 14:525-33; PMID:23578722; http://dx.doi.org/10.1016/S1470- 2045(13)70122-0
82. Pfreundschuh M, Zeynalova S, Poeschel V, Haenel M, Scmitz N, Ho D, Reiser M, Loeffler M, Schubert J. Improved outcome of elderly patients with poor prognosis diffuse large B-cell lymphoma (DLBCL) after dose-dense rituximab: Results of the DENSE-R-CHOP-14 trial of the german High Grade Non Hodgkin's Lymphoma Study Group (DSHNHL). J Clin Oncol 2008; 26:a8508
83. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377:42-51; PMID:21176949; http://dx.doi.org/10.1016/S0140-6736(10) 62175-7
84. Kahl BD, Williams ME, Hong F, Gascoyne RD, Horning SJ. Preliminary pharmacokinetic (PK) analysis of eastern cooperative oncology group protocol E4402: rituximab extended schedule or re-treatment trial (RESORT). Blood 2007; 110:3420a
85. Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, Lu D, et al. A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet 2012; 51:119-35; PMID:22257150; http://dx.doi.org/10.2165/ 11596370-000000000-00000
86. Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009; 49:1012-24; PMID:19620385; http://dx.doi. org/10.1177/ 0091270009337512
87. Dall'Ozzo S, Tartas S, Paintaud G, Cartron G, Colombat P, Bardos P, Watier H, Thibault G. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res 2004; 64:4664-9; PMID:15231679; http://dx.doi.org/10.1158/0008-5472. CAN-03-2862
88. Wang SY, Racila E, Taylor RP, Weiner GJ. NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement. Blood 2008; 111:1456-63; PMID:18024795; http://dx.doi. org/10.1182/blood-2007-02-074716
89. Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 2001; 98:3383-9; PMID:11719378; http://dx.doi.org/10.1182/blood.V98.12.3383
90. Macor P, Tripodo C, Zorzet S, Piovan E, Bossi F, Marzari R, Amadori A, Tedesco F. In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab. Cancer Res 2007; 67:10556-63; PMID:17975000; http://dx.doi.org/10.1158/0008-5472.CAN-07- 1811
91. Dalle S, Dupire S, Brunet-Manquat S, Reslan L, Plesa A, Dumontet C. In vivo model of follicular lymphoma resistant to rituximab. Clin Cancer Res 2009; 15:851- 7; PMID:19188155; http://dx.doi.org/10.1158/1078-0432.CCR-08-1685
92. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21:3940- 7; PMID:12975461; http://dx.doi.org/10. 1200/JCO.2003.05.013
93. Cartron G, Trappe RU, Solal-Céligny P, Hallek M. Interindividual variability of response to rituximab: from biological origins to individualized therapies. Clin Cancer Res 2011; 17:19-30; PMID:21208903; http://dx.doi.org/10. 1158/1078-0432.CCR-10-1292
94. Ternant D, Cartron G, Hénin E, Tod M, Girard P, Paintaud G. Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma. Br J Clin Pharmacol 2012; 73:597-605; PMID:21999172; http://dx.doi.org/10.1111/j.1365-2125.2011.04125.x
95. Farag SS, Flinn IW, Modali R, Lehman TA, Young D, Byrd JC. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 2004; 103:1472-4; PMID:14563637; http://dx.doi.org/10.1182/blood-2003-07-2548
96. Carlotti E, Palumbo GA, Oldani E, Tibullo D, Salmoiraghi S, Rossi A, Golay J, Pulsoni A, Foà R, Rambaldi A. FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab. Haematologica 2007; 92:1127-30; PMID:17650444; http://dx.doi.org/10.3324/haematol.11288
97. Ahlgrimm M, Pfreundschuh M, Kreuz M, Regitz E, Preuss KD, Bittenbring J. The impact of Fc-γ receptor polymorphisms in elderly patients with diffuse large B-cell lymphoma treated with CHOP with or without rituximab. Blood 2011; 118:4657-62; PMID:21900198; http://dx.doi.org/10.1182/blood-2011-04-346411
98. Lejeune J, Thibault G, Ternant D, Cartron G, Watier H, Ohresser M. Evidence for linkage disequilibrium between Fcgamma RIIIa-V158F and Fcgamma RIIa- H131R polymorphisms in white patients, and for an Fcgamma RIIIa-restricted influence on the response to therapeutic antibodies. J Clin Oncol 2008; 26:5489- 91, author reply 5491-2; PMID:18955438; http://dx.doi.org/10.1200/JCO. 2008.19.4118
99. Danielou-Lazareth A, Henry G, Geromin D, Khaznadar Z, Briere J, Tamouza R, Cayuela JM, Thieblemont C, Toubert A, Dulphy N. At diagnosis, diffuse large B-cell lymphoma patients show impaired rituximab-mediated NK-cell cytotoxicity. Eur J Immunol 2013; 43:1383-8; PMID:23400905; http://dx.doi.org/10.1002/eji. 201242733
100. Taskinen M, Karjalainen-Lindsberg ML, Nyman H, Eerola LM, Leppä S. A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide- doxorubicin-vincristine-prednisone. Clin Cancer Res 2007; 13:5784-9; PMID:17908969; http://dx.doi.org/10.1158/1078-0432.CCR-07-0778
101. Beurskens FJ, Lindorfer MA, Farooqui M, Beum PV, Engelberts P, Mackus WJ, Parren PW, Wiestner A, Taylor RP. Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients. J Immunol 2012; 188:3532-41; PMID:22368276; http://dx.doi.org/10.4049/jimmunol.1103693
102. van der Kolk LE, Grillo-López AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol 2001; 115:807-11; PMID:11843813; http://dx.doi.org/10. 1046/j.1365-2141.2001.03166.x
103. Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol 2004; 172:3280-8; PMID:14978136
104. Aue G, Lindorfer MA, Beum PV, Pawluczkowycz AW, Vire B, Hughes T, Taylor RP, Wiestner A. Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia. Haematologica 2010; 95:329-32; PMID:19679883; http://dx.doi.org/10. 3324/haematol.2009.012484
105. Lindorfer MA, Wiestner A, Zent CS, Taylor RP. Monoclonal antibody (mAb)-based cancer therapy: Is it time to reevaluate dosing strategies? Oncoimmunology 2012; 1:959-61; PMID:23162771; http://dx.doi.org/10.4161/onci. 20368