TriFabs—Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery

Mayer, Klaus; Baumann, Anna-Lena; Grote, Michael; Seeber, Stefan; Kettenberger, Hubert; Breuer, Sebastian; Killian, Tobias; Schäfer, Wolfgang; Brinkmann, Ulrich

doi:10.3390/ijms161126037

Cited by 19 publications

(20 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2, box 9 ). 109 TriFabs harbor two regular Fabs fused through flexible 20-residue peptide linkers, (G 4 S) 4 , to an asymmetric Fab-like entity as heterodimerization module (stem region). The latter is composed of a VH fused to a CH3 domain with a knob mutation (T366W) and a VL domain fused to a CH3 domain with matching hole mutations (T366S, L368A, Y407V) (see 3.2).…”

Section: Fc-less Bispecific Antibody Formatsmentioning

confidence: 99%

The making of bispecific antibodies

Brinkmann

Kontermann

2017

mAbs

Self Cite

740

706

View full text Add to dashboard Cite

During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The 'zoo' of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigenbinding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties. These parameters may be summarized under the term 'developability'. In addition, different 'target product profiles', i.e., desired features of the bispecific antibody to be generated, mandates the need for access to a diverse panel of formats. These may vary in size, arrangement, valencies, flexibility and geometry of their binding modules, as well as in their distribution and pharmacokinetic properties. There is not 'one best format' for generating bispecific antibodies, and no single format is suitable for all, or even most of, the desired applications. Instead, the bispecific formats collectively serve as a valuable source of diversity that can be applied to the development of therapeutics for various indications. Here, a comprehensive overview of the different bispecific antibody formats is provided.

show abstract

Section: Fc-less Bispecific Antibody Formatsmentioning

confidence: 99%

The making of bispecific antibodies

Brinkmann

Kontermann

2017

mAbs

Self Cite

740

706

View full text Add to dashboard Cite

show abstract

“…Furthermore, we report that for one VHH analyzed (HER2) in this platform approach, engraftment onto the kappa chain causes a substantial loss of affinity when the other embedded VHH (EGFR, clone 9G8) already engages in antigen binding. Positioning effects have also been described for other bispecific platform technologies, for instance, DVD-Igs or TriFabs and others, 34,[38][39][40] typically resulting in compromised binding affinities. Surprisingly, the individual binding affinity of the engrafted paratope against the respective antigen was not impaired substantially.…”

Section: Namementioning

confidence: 99%

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Pekar

Busch

Valldorf

et al. 2020

mAbs

View full text Add to dashboard Cite

Here, we report the characterization of a VHH-derived IgG-like bi-and trispecific antibody platform that essentially relies on the replacement of the VH and VL regions of a conventional antibody by two independently functioning VHH domains. Consequently, a VHH is engrafted onto constant region CH1 while the other VHH-based paratope is engrafted on the constant region of the light chain, Cκ or Cλ, resulting in a tetravalent bispecific IgG-like molecule. Combined with a heavy chain heterodimerization technique, this platform allows facile engineering of bi-and trispecific antibodies with flexible valencies. We demonstrate the general applicability of this generic platform approach and elaborate on the limitations of specific formats.

show abstract

“…Osteopontin overexpression was associated with vascular invasion, tumor metastasis, and poor prognosis [79, 82, 84]. …”

Section: Figurementioning

confidence: 99%

“…Another bispecific antibody named trivalent IgG-Shaped (TriFab) construct was developed by fusing two anti-GPC3 Fab fragments via a flexible linker to one asymmetric third Fab-sized binding domain [79]. The bivalent Fab arms bind GPC3 with similar affinity of the parent IgG antibody.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies

Hoseini

Cheung

2017

Cancer Letters

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.

show abstract

TriFabs—Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery

Cited by 19 publications

References 30 publications

The making of bispecific antibodies

The making of bispecific antibodies

Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform

Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies

Contact Info

Product

Resources

About