Bispecific antibody conjugates in therapeutics

Cao, Ying; Lam, Laura

doi:10.1016/s0169-409x(02)00178-3

Cited by 79 publications

(54 citation statements)

References 155 publications

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“…BsAb can bind simultaneously to tumor-associated antigens (eg Pgp) on tumor cell surface and triggering molecules on the effector cells, leading to effector cell activation and subsequent tumor killing. 18,19 Several markers on effector cell surface, such as CD2 and CD3 on T cells, CD16 on natural killer cells, CD64 on macrophages and granulocytes, have been used for effector cell targeting and activation. 18,19 A number of BsAb have demonstrated potent antitumor efficacy both in vitro and in animal models as well as in several small-scale clinic trials.…”

Section: Introductionmentioning

confidence: 99%

Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody

et al. 2004

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Section: Introductionmentioning

confidence: 99%

Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody

et al. 2004

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“…By cross-linking tumor and effector cells, the BsAb not only brings the effector cells within the proximity of the tumor cells but also simultaneously triggers their activation, leading to effective tumor cell-killing. Preliminary but promising clinical benefits have been observed in a number of early stage trials [21] . In addition, BsAb has also been used to enrich the tumor/normal tissue localization ratio of chemoor radiotherapeutic agents.…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

“…In this setting, one arm of the BsAb binds an antigen expressed on the cell targeted for destruction, and the other arm binds a chemotherapeutic drug, radioisotope, or toxin. The naked BsAb is administered first, and after sufficient time has passed for the BsAb to bind tumor cells and to clear from normal tissue, the cytotoxic molecule is delivered, with rapid accumulation in the tumor, because of its affinity for the tumor bound BsAb [21][22][23][24][25] . Recently, a novel concept has emerged -the development of BsAb that target two tumor-associated antigens (eg, growth factor receptors) for down-regulation of multiple distinct cell proliferation/survival pathways, which provides enhanced antitumor activity [26][27][28] .…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Recombinant approaches to IgG-like bispecific antibodies

Marvin¹,

Zhu²

2005

Acta Pharmacologica Sinica

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One of the major obstacles in the development of bispecific antibodies (BsAb) has been the difficulty of producing the materials in sufficient quality and quantity by traditional technologies, such as the hybrid hybridoma and chemical conjugation methods. In contrast to the rapid and significant progress in the development of recombinant BsAb fragments (such as diabody and tandem single chain Fv), the successful design and production of full length IgG-like BsAb has been limited. Compared to smaller fragments, IgG-like BsAb have long serum halflife and are capable of supporting secondary immune functions, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. The development of IgG-like BsAb as therapeutic agents will depend heavily on our research progress in the design of recombinant BsAb constructs (or formats) and production efficiency. This review will focus on recent advances in various recombinant approaches to the engineering and production of IgG-like BsAb.

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“…This bispecificity can be applied to cancer immunotherapy by cross-linking tumor cells to immune cells, such as cytotoxic T cells, natural killer cells, and macrophages. This linkage accelerates the destruction of the tumor cells by immune cells, so that compared to monospecific antibodies, the therapeutic dose can be lower (8,9).…”

Section: Introductionmentioning

confidence: 99%

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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Bispecific antibody conjugates in therapeutics

Cited by 79 publications

References 155 publications

Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody

Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein × anti-CD3 diabody

Recombinant approaches to IgG-like bispecific antibodies

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

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