Top

Published in:

Open Access 01-08-2009 | Original Article

Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγ^null mouse model

Authors: Asahi Ito, Takashi Ishida, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Fumihiko Sato, Hisashi Takino, Fumiko Mori, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda

Published in: Cancer Immunology, Immunotherapy | Issue 8/2009

Abstract

Purpose

There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials.

Experimental design

NOD/Shi-scid, IL-2Rγ^null (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors.

Results

Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice.

Conclusions

Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy.

Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242PubMedCrossRef

Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M, Group MabTheraInternationalTrial (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391PubMedCrossRef

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRef

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRef

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRef

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578PubMedCrossRef

Smith MR (2003) Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 22:7359–7368PubMedCrossRef

Carter P (2001) Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1:118–129PubMedCrossRef

Glennie MJ, van de Winkel JG (2003) Renaissance of cancer therapeutic antibodies. Drug Discov Today 8:503–510PubMedCrossRef

10.

Ishida T, Ueda R (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139–1146PubMedCrossRef

11.

Voso MT, Pantel G, Rutella S, Weis M, D’Alò F, Urbano R, Leone G, Haas R, Hohaus S (2002) Rituximab reduces the number of peripheral blood B-cells in vitro mainly by effector cell-mediated mechanisms. Haematologica 87:918–925PubMed

12.

Clynes RA, TowersTL PrestaLG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446PubMedCrossRef

13.

Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgRIIIa gene. Blood 99:754–758PubMedCrossRef

14.

Ishida T, Ishii T, Inagaki A, Yano H, Kusumoto S, Ri M, Komatsu H, Iida S, Inagaki H, Ueda R (2006) The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma. Leukemia 20:2162–2168PubMedCrossRef

15.

Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, Matsushima K, Ueda R, Hanai N, Shitara K (2004) Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res 64:2127–2133PubMedCrossRef

16.

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T (2002) NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100:3175–3182PubMedCrossRef

17.

Ito M, Kobayashi K, Nakahata T (2008) NOD/Shi-scid IL2rγ^null (NOG) mice more appropriate for humanized mouse models. Curr Top Microbiol Immunol 324:53–76PubMedCrossRef

18.

Armitage J, Vose J, Weisenburger D (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26:4124–4130PubMedCrossRef

19.

Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K, Ueda R (2003) Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma (ATLL): its close association with skin involvement and unfavorable outcome. Clin Cancer Res 9:3625–3634PubMed

20.

Ishida T, Inagaki H, Utsunomiya A, Takatsuka Y, Komatsu H, Iida S, Takeuchi G, Eimoto T, Nakamura S, Ueda R (2004) CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified. Clin Cancer Res 10:5494–5500PubMedCrossRef

21.

Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki M, Hanai N, Shitara K (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278:3466–3473PubMedCrossRef

22.

Ishida T, Iida S, Akatsuka Y, Ishii T, Miyazaki M, Komatsu H, Inagaki H, Okada N, Fujita T, Shitara K, Akinaga S, Takahashi T, Utsunomiya A, Ueda R (2004) The CC chemokine receptor 4 as a novel-specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. Clin Cancer Res 10:7529–7539PubMedCrossRef

23.

Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R (2006) Specific recruitment of CCR4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 66:5716–5722PubMedCrossRef

24.

Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, Nakamura K, Shitara K (2005) Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. Clin Cancer Res 11:2327–2336PubMedCrossRef

25.

Yano H, Ishida T, Imada K, Sakai T, Ishii T, Inagaki A, Iida S, Uchiyama T, Ueda R (2008) Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF. Br J Haematol 140:586–589PubMedCrossRef

26.

Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D’Ambrosio D (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 194:847–853PubMedCrossRef

27.

Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS (2006) The majority of human peripheral blood CD4 + CD25highFoxp3 + regulatory T cells bear functional skin-homing receptors. J Immunol 177:4488–4494PubMed

28.

Baatar D, Olkhanud P, Sumitomo K, Taub D, Gress R, Biragyn A (2007) Human peripheral blood T regulatory cells (Tregs), functionally primed CCR4 + Tregs and unprimed CCR4− Tregs, regulate effector T cells using FasL. J Immunol 178:4891–4900PubMed

29.

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedCrossRef

30.

Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R (2007) Defucosylated anti CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/refractory mycosis fungoides and Sezary syndrome. Clin Cancer Res 13:6494–6500PubMedCrossRef

31.

Nadali G, Tavecchia L, Zanolin E, Bonfante V, Viviani S, Camerini E, Musto P, Di Renzo N, Carotenuto M, Chilosi M, Krampera M, Pizzolo G (1998) Serum level of the soluble form of the CD30 molecule identifies patients with Hodgkin’s disease at high risk of unfavorable outcome. Blood 91:3011–3016PubMed

32.

Zinzani PL, Pileri S, Bendandi M, Buzzi M, Sabattini E, Ascani S, Gherlinzoni F, Magagnoli M, Albertini P, Tura S (1998) Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients. J Clin Oncol 16:1532–1537PubMed

33.

Younes A, Consoli U, Snell V, Clodi K, Kliche KO, Palmer JL, Gruss HJ, Armitage R, Thomas EK, Cabanillas F, Andreeff M (1997) CD30 ligand in lymphoma patients with CD30 + tumors. J Clin Oncol 15:3355–3362PubMed

34.

Snanoudj R, Rouleau M, Bidère N, Carmona S, Baron C, Latinne D, Bazin H, Charpentier B, Senik A (2004) A role for CD2 antibodies (BTI-322 and its humanized form) in the in vivo elimination of human T lymphocytes infiltrating an allogeneic human skin graft in SCID mice: an Fcgamma receptor-related mechanism involving co-injected human NK cells. Transplantation 78:50–58PubMedCrossRef

35.

Zhang Z, Zhang M, Ravetch JV, Goldman C, Waldmann TA (2003) Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507. Blood 102:284–288PubMedCrossRef

36.

Zhang Z, Zhang M, Goldman CK, Ravetch JV, Waldmann TA (2003) Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H. Cancer Res 63:6453–6457PubMed

37.

Zhang M, Zhang Z, Garmestani K, Goldman CK, Ravetch JV, Brechbiel MW, Carrasquillo JA, Waldmann TA (2004) Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult T-cell leukemia. Cancer Res 64:5825–5829PubMedCrossRef

38.

Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A (2002) Human natural killer cells: their origin, receptors and function. Eur J Immunol 32:1205–1211PubMedCrossRef

39.

Niwa R, Hatanaka S, Shoji-Hosaka E, Sakurada M, Kobayashi Y, Uehara A, Yokoi H, Nakamura K, Shitara K (2004) Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 is independent of FcgRIIIa functional polymorphism. Clin Cancer Res 10:6248–6255PubMedCrossRef

40.

Zou W (2006) Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRef

41.

Zou W (2005) Immunosuppressive networks in the tumor environment and their therapeutic relevance. Nat Rev Cancer 5:263–274PubMedCrossRef

42.

Finn OJ (2008) Cancer immunology. N Engl J Med 358:2704–2715PubMedCrossRef

43.

Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 105:3005–3010PubMedCrossRef

44.

Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Hughes M, Yellin MJ, Haworth LR, Levy C, Allen T, Mavroukakis SA, Attia P, Rosenberg SA (2006) Intrapatient dose escalation of anti-CTLA–4 antibody in patients with metastatic melanoma. J Immunother 29:455–463PubMedCrossRef

45.

Sanderson K, Scotland R, Lee P, Liu D, Groshen S, Snively J, Sian S, Nichol G, Davis T, Keler T, Yellin M, Weber J (2005) Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741–750PubMedCrossRef

46.

Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107:159–166PubMedCrossRef

Title: Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model
Authors: Asahi Ito
Takashi Ishida
Hiroki Yano
Atsushi Inagaki
Susumu Suzuki
Fumihiko Sato
Hisashi Takino
Fumiko Mori
Masaki Ri
Shigeru Kusumoto
Hirokazu Komatsu
Shinsuke Iida
Hiroshi Inagaki
Ryuzo Ueda
Publication date: 01-08-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 8/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0632-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Experimental design

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2009

Breast cancer cells expressing stem cell markers CD44+ CD24lo are eliminated by Numb-1 peptide-activated T cells

The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer

TGF-alpha as a candidate tumor antigen for renal cell carcinomas

Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases

Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains

Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines

Keynote webinar | Spotlight on antibody–drug conjugates in cancer