Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: A pre-clinical study

Pfosser, Achim; Brandl, Martina; Salih, Helmut R.; Grosse‐Hovest, Ludger; Jung, Gundram

doi:10.1002/(sici)1097-0215(19990209)80:4<612::aid-ijc21>3.0.co;2-k

Cited by 25 publications

(13 citation statements)

References 12 publications

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“…No recurrences occurred during 10—18 months of follow-up in the 8 patients showing partial or complete response. Subsequently, others have reported the use of different BiAbs both in vitro and early-stage clinical trials [41-46]. …”

Section: Discussionmentioning

confidence: 99%

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

et al. 2013

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BackgroundSince most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2.MethodsATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines.ResultsEGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets.ConclusionHigh-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens.

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Section: Discussionmentioning

confidence: 99%

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

et al. 2013

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“…isolated by density-gradient centrifugation from a healthy volunteer were cultured for 48 h in a culture medium supplemented with 100 IU/ml recombinant human interleukin 2 (IL-2), kindly supplied by Shionogi & Co., Ltd., (Osaka, Japan) at a cell density of 1x10 6 /ml in a culture flask (Nunc A/S, Roskilde, Denmark) pre-coated with OKT3 monoclonal antibody (10 µg/ml). The proliferated cells were then transferred to another flask and expanded in a culture medium containing 100 IU/ml IL-2 for 2-3 weeks, as previously reported (28).…”

Section: Preparation and Stimulation Of Effector Cells For The Inducmentioning

confidence: 99%

“…In vivo tumor models. Female 8-week-old severe combined immunodeficient (SCID) mice (Fox CHASE C.B.-17/Icr-Scid Jcr) (Clea Japan, Inc., Tokyo, Japan) were injected with 5x10 6 TFK-1 cells subcutaneously into the dorsal thoracic wall on day 0. Using these mice, we evaluated three models of efficacy.…”

Section: Preparation and Stimulation Of Effector Cells For The Inducmentioning

confidence: 99%

“…In the third model, we compared the antitumor activity of hEx3-Db with the IgG-like BsAbs. Ten days after the initial TFK-1 injection, hEx3-Db (20 µg), hEx3-scDb-Fc (20 µg), or hEx3-scFv-Fc (20 µg) were injected intravenously via the tail vein on 4 consecutive days (days 1, 2, 3 and 4) with or without effector cells [T-LAK cells (2.0x10 6 ) or PBMCs (4.0x10 6 )] and IL-2 (250 IU). In this experiment we used 2.0x10 6 T-LAK cells to mimic physiological conditions.…”

Section: Preparation and Stimulation Of Effector Cells For The Inducmentioning

confidence: 99%

“…Previous reports have demonstrated that EGFR is widely expressed in a variety of solid tumors, and its expression level is correlated with malignancy, metastatic phenotype, and poor prognosis (1)(2)(3). Two anti-EGFR therapeutic antibodies, cetuximab and panitumumab, have already been approved by the US Food and Drug Administration, and several bispecific antibodies (BsAbs) that target EGFR are in development (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo antitumor effects of recombinant bispecific antibodies based on humanized anti-EGFR antibody

Watanabe

Asano

Arai³

et al. 2011

Oncol Rep

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Abstract. We performed in vitro and in vivo experiments of the anti-epidermal growth factor receptor (EGFR) x anti-CD3 bispecific diabody (hEx3-Db) with the IgG-like bispecific antibodies (BsAbs) (hEx3-scFv-Fc and hEx3-scDb-Fc) and the anti-EGFR therapeutic antibody cetuximab to assess the effect of BsAbs on cancer growth inhibition. In vitro, efficacy of the BsAbs and cetuximab were compared by growth inhibition assays of human cell lines of bile duct (TFK-1, HuCC-T1, OCUCh-LM1), epidermoid (A431), gastric (Kato-III), colon (DLD-1, SW480), and breast (SK-BR-3, MCF-7) cancer. In vivo, in three mouse models, we evaluated the anti-tumor activity of hEx3-Db and cetuximab, assessed the effect of hEx3-Db alone, and compared the antitumor activity of hEx3-Db with the IgG-like BsAbs. In vitro, hEx3-scFv-Fc showed nearly 100% killing activity for all cell lines. Both in vitro and in vivo, hEx3-Db needed CD3-positive phenotypes to induce a growth inhibitory effect. In contrast, IgG-like BsAbs showed monotherapeutic effects in vivo by inducing antibody-dependent cellular cytotoxicity (ADCC) similar to cetuximab. However, enhancement was not observed when lymphokine-activated killer cells with the T-cell phenotype were co-injected. Results suggest that IgG-like BsAbs could not efficiently direct T lymphocytes toward tumor cells to induce ADCC due to steric hindrance on binding to CD3-and Fc-receptor-positive phenotypes. Although hEx3-scFv-Fc showed high cytotoxicity in vitro, its high molecular weight limits its usefulness. With an in vivo effect comparable to hEx3-scFv-Fc and its realistic molecular weight, hEx3-scDb-Fc shows promise as a novel recombinant therapeutic antibody and may be modified to enhance its potency by prevention of steric hindrance.

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Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: Evidence forin situT-cell activation and therapeutic efficacy

Jung

Brandl²,

Eisner³

et al. 2000

Int. J. Cancer

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Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: A pre-clinical study

Cited by 25 publications

References 12 publications

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

In vitro and in vivo antitumor effects of recombinant bispecific antibodies based on humanized anti-EGFR antibody

Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: Evidence forin situT-cell activation and therapeutic efficacy

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