Characterization of novel murine anti-CD20 monoclonal antibodies and their comparison to 2B8 and c2B8 (rituximab)

Nishida, Minoru; Usuda, S; Okabe, Masato; Miyakoda, Hiroko; Komatsu, Midori; Hanaoka, Hiroshi; Teshigawara, Keisuke; Niwa, Osami

doi:10.3892/ijo.31.1.29

Cited by 16 publications

(24 citation statements)

References 25 publications

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“…In all other cases of murine-derived mAbs, the heavy chain V region genes were derived from the VH1 family genes (13,28). These include 2B8, 2H7, 1F5, A20, B1 and B-Ly1 and most of other cases of the light chain V region genes were from Vκ4/5 family genes except for B-Ly1 which was Vκ24/25.…”

Section: Discussionmentioning

confidence: 99%

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

Nishida

Uematsu²,

Kobayashi³

et al. 2011

Int J Oncol

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Abstract. Rituximab (chimeric anti-CD20 mAb) is currently used in the treatment of B-NHL and B cell malignancies, alone or in combination with chemotherapy. However, subsets of patients do not initially respond and/or develop resistance to additional treatments. Hence, there is a need to develop more effective anti-CD20 mAbs that may improve clinical response. BM-ca is a novel humanized anti-CD20 mAb that was tested against several B-NHL cell lines and was compared to several anti-CD20 mAbs (Rituximab, ofatumumab, 2H7, B1 and B-Ly1). BM-ca was shown to strongly induce both homotypic cell aggregation and redistribution of CD20 to membrane lipid rafts. BM-ca was also able to induce programmed cell death (apoptosis) without the need for cross-linking and demonstrated potent complement-dependent cytotoxicity (CDC). BM-ca was more cytotoxic than rituximab even in malignant B cells expressing low amounts of membrane CD20. Type I anti-CD20 mAbs typically induce minimal levels of homotypic cell aggregation and apoptosis but strong localization of CD20 to lipid rafts and potent CDC. Type II anti-CD20 mAbs typically exert the reverse activities. Noteworthy, BM-ca exhibits properties that are shared by both type I and type II anti-CD20 mAbs, which may reflect the recognition of a new CD20 epitope and/or exhibit different molecular signaling. Overall, the present data show that BM-ca is a novel anti-CD20 mAb that may be classified as a type I/II. The therapeutics efficacy of BM-ca awaits its use in clinical trials. IntroductionThe use of rituximab as a single agent or in combination with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP), is now a standard therapy for nonHodgkin's lymphoma (NHL) (1,2). NHL patients do not always completely respond to rituximab therapy, however, and a subset of patients who initially responded become resistant or less responsive to further treatment (3). Despite a great number of reports, the in vivo mechanisms responsible to predict the clinical outcome in NHL after anti-CD20 treatment remain elusive. Complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis are all potential cytotoxic mechanisms, although it is unclear which mechanism is important in vivo. Redistribution of CD20 to membrane lipid rafts by anti-CD20 results in the clustering of antibody molecules and enhancing C1q binding, the first step in the CDC induction mechanism (4). In addition to these above cytotoxic mechanisms, homotypic cell aggregation has been reported to be involved in antibody-induced cytotoxicity as well as the induction of apoptosis (5-7).CD20 antibodies have been classified as type I or type II depending on their functional characteristics. Type I exhibits strong CDC activity but weak apoptosis whereas type II shows the opposite, i.e., weak CDC and strong apoptosis. Type I antibodies have the ability to redistribute CD20 to membrane lipid rafts whereas type II do not. Further, type I induce little homotypic cell aggregation whereas homotypic ce...

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Section: Discussionmentioning

confidence: 99%

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

Nishida

Uematsu²,

Kobayashi³

et al. 2011

Int J Oncol

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“…hOUBM3 and hOUBM6 are humanized versions of the murine antibodies 1k1782 and 1k1791 that were previously identified as having properties and epitope specificities different from rituximab and ibritumomab. 83 In preclinical studies, variants of hOUBM6 showed higher CDC levels, similar or higher ADCC levels and similar depletion of leukemia and lymphoma cells compared with rituximab. 75 Residues A170 and P172 of CD20 are not essential for binding of hOUBM3 and hOUBM6, suggesting that the epitope for these antibodies indeed differs from that of rituximab.…”

Section: Type II Cd20 Antibodiesmentioning

confidence: 99%

“…Recent work with TNFR agonistic antibodies including CD40 and DR5 antibodies has shown that binding to CD40 and FcγRIIb in cis is required to mediate potent CD40 or DR5 activation. [83][84][85] We propose that Type I CD20 antibodies bind to CD20 on B cells in a conformation that allows simultaneous binding to FcγRIIb on the same cell (in cis) resulting in crosslinking, FcγRIIb co-activation and CD20 co-internalization upon binding potentially in lipid rafts. Vice versa, the biological effects could be explained by the different binding conformation of Type II CD20 antibodies that might prevent simultaneous binding in cis to FcγRIIB, which precludes FcγRIIb crosslinking and CD20 co-internalization (Fig.…”

Section: Type II Cd20 Antibodiesmentioning

confidence: 99%

Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties

Klein

Lammens

Schäfer

et al. 2013

mAbs

303

294

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“…the IL-15N72D⅐IL-15R␣SuFc complex) could also function as a protein scaffold to create multispecific IL-15-based targeted immunotherapeutic agents. To test this, we converted the variable regions of the heavy and light chains of rituximab into an scFv (sc2B8) (9) and genetically fused sc2B8 to the N termini of IL-15N72D and IL-15R␣SuFc proteins of ALT-803. Based on the high binding affinity between the IL-15N72D and IL-15R␣Su domains, we expected the fusion proteins to form a heterodimeric complex between sc2B8-IL-15N72D and sc2B8-IL-15R␣SuFc.…”

Section: Creation Of Multifunctional Protein Complexes Using the Il-1mentioning

confidence: 99%

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

Liu

Kong

Han

et al. 2016

Journal of Biological Chemistry

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Edited by Luke O'Neill IL-15 and its receptor ␣ (IL-15R␣IL-15, a four-helix, common ␥ chain (␥ C ) 2 cytokine, is a critical factor for the development, proliferation, and activation of natural killer (NK) cells and CD8 ϩ T cells (1, 2). IL-15 is co-expressed with its ␣ chain receptor (IL-15R␣) by antigen-presenting cells, and the two proteins form a complex on the cell surface that is transpresented to NK and T cells bearing the IL-2R␤␥ C complex (2). IL-15 binds to IL-15R␣ at high affinity, and IL-15R␣ functions as a chaperone and conformational stabilizer to enhance the interaction between IL-15 and IL-2R␤␥ C (2). We identified a novel IL-15 variant carrying an asparagineto-aspartic acid mutation at amino acid 72 (N72D) that exhibits superior binding to IL-2R␤␥ C on immune cells and increased immunostimulatory activity (3). Our previous studies have demonstrated that this IL-15 variant, when associated with a soluble IL-15R␣ sushi domain fusion to IgG1 Fc (IL15R␣SuFc), could form a heterodimeric complex, IL-15N72D⅐ IL-15R␣SuFc (designated ALT-803), that also exhibits increased binding activity to the IL-2R␤␥ C complex, enhanced capacity to stimulate NK and T cells, and has a longer biological half-life compared with native IL-15 (4). In various animal models, ALT-803 acts as a potent immunostimulant that is capable of simultaneously activating the innate and adaptive arms of the immune system to elicit both rapid and long-lasting protective responses against neoplastic challenges (5). Moreover, ALT-803, in combination with checkpoint blockade or therapeutic antibodies, is effective in reducing the tumor burden and prolonging survival in mouse tumor models (6, 7). To make ALT-803-based molecules more specific and efficient in combating disease, we converted ALT-803 into a targeted immunotherapeutic agent by genetically fusing it with singlechain antibodies (scFv) at the N termini of IL-15N72D and IL-15R␣SuFc proteins. In this study, we used the anti-CD20 scFv as the target recognition domain to demonstrate that ALT-803 is a versatile, functional scaffold for creating diseasetargeted immunostimulatory molecules. This novel single fusion protein approach was also found to improve the antibody-dependent cellular cytotoxicity (ADCC) and apoptotic functions of the anti-CD20 therapeutic antibody rituximab.

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Characterization of novel murine anti-CD20 monoclonal antibodies and their comparison to 2B8 and c2B8 (rituximab)

Cited by 16 publications

References 25 publications

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

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