Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics

Kipriyanov, Sergey M.; Moldenhauer, Gerhard; Schuhmacher, Jochen; Cochlovius, Björn; Lieth, C.W. von der; Matys, Eva; Little, Melvyn

doi:10.1006/jmbi.1999.3156

Cited by 180 publications

(130 citation statements)

References 62 publications

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“…23 Its derivatives include, but are not limited to, dsDb (interchain disulfide bond between V L and V H of the same antibody), 24 DART (dual-affinity re-targeting, interchain disulfide bond between 2 V L ), 25 scDb (single chain Diabody), 26 and tandAbs (Diabody dimer via flexible linkers in between). 27 The other is the BiTE Ò (bispecific T-cell engager), which is composed of 2 scFvs connected in tandem by an adjustable linker. 28 Because of their unique structural features, the more compact Diabody is often employed as a diagnostic tool or drug delivery vehicle, 29 while BiTEs are generally developed as anti-cancer therapeutics to co-localize T cells and tumor cells to form immunologic synapses and therefore trigger tumor cell cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system

Lee

Tran

et al. 2015

mAbs

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(2015) Production of bispecific antibodies in "knobs-into-holes" using a cell-free expression system , mAbs, 7:1, 231-242, DOI: 10.4161/19420862.2015.989013 To link to this article: https://doi.org/10. 4161/19420862.2015 Bispecific antibodies have emerged in recent years as a promising field of research for therapies in oncology, inflammable diseases, and infectious diseases. Their capability of dual target recognition allows for novel therapeutic hypothesis to be tested, where traditional mono-specific antibodies would lack the needed mode of target engagement. Among extremely diverse architectures of bispecific antibodies, knobs-into-holes (KIHs) technology, which involves engineering C H 3 domains to create either a "knob" or a "hole" in each heavy chain to promote heterodimerization, has been widely applied. Here, we describe the use of a cell-free expression system (Xpress CF) to produce KIH bispecific antibodies in multiple scaffolds, including 2-armed heterodimeric scFv-KIH and one-armed asymmetric BiTE-KIH with tandem scFv. Efficient KIH production can be achieved by manipulating the plasmid ratio between knob and hole, and further improved by addition of prefabricated knob or hole. These studies demonstrate the versatility of Xpress CF in KIH production and provide valuable insights into KIH construct design for better assembly and expression titer.

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Section: Introductionmentioning

confidence: 99%

Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system

Lee

Tran

et al. 2015

mAbs

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“…To overcome some of the remaining weaknesses of this format, such as an unfavourable plasma retention, the format has been further improved by expanding it to tandem diabodies (Kipriyanov et al, 1999) and singlechain triplebodies (sctbs; Kellner et al, 2008). The incorporation of a second scFv-binding site for tumour-antigens in these extended formats has led to increased avidity for the tumour cell, increased anti-tumour activity in antibody-dependent cellular cytotoxicity (ADCC) reactions, and improved plasma retention in vivo (Kellner et al, 2008).…”

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confidence: 99%

A recombinant trispecific single‐chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting

et al. 2010

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Two trivalent constructs consisting of single-chain Fv antibody fragments (scFvs) specific for the interleukin-3 receptor a chain (CD123), CD33 and the Fcc-receptor III (CD16) were designed and characterized for the elimination of acute myeloid leukaemia (AML) cells. The dual targeting single-chain Fv triplebody (sctb) [123 · ds16 · 33] and the mono targeting sctb [123 · ds16 · 123] both specifically bound their respective target antigens and were stable in human serum at 37°C for at least 5 d. Both constructs induced potent antibody-dependent cellular cytotoxicity (ADCC) of two different AML-derived CD33-and CD123 double-positive cell lines in the low picomolar range using isolated mononuclear cells (MNCs) as effector cells. In these experiments the dual targeting molecule produced significantly stronger lysis than the mono targeting agent. In addition, the sctbs showed a high potency in mediating ADCC of primary leukaemia cells isolated from peripheral blood or bone marrow of seven AML patients. Hence, these novel molecules displayed potent anti-leukaemic effects against AML cells in vitro and represent attractive candidates for further preclinical development.

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“…Single chain diabody-Fc fusion Kipriyanov et al have developed a "single chain" diabody (scDb) by fusing both "cross-over" scFv of a bispecific diabody with a flexible linker [47] . This construct is fused to an Fc fragment (or just a CH3 domain) to create a tetravalent bispecific IgG-like molecule ( Figure 2).…”

Section: Recombinant Approaches To Igg or Igg-like Bsabmentioning

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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Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics

Cited by 180 publications

References 62 publications

Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system

Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system

A recombinant trispecific single‐chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting

Recombinant approaches to IgG-like bispecific antibodies

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