Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule

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.

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“…2, box 9 ). 180 This biparatopic antibody demonstrated enhanced activity, similar to the combination of the two parental antibodies.…”

Section: Bispecific Iggs With Asymmetric Architecturementioning

confidence: 83%

The making of bispecific antibodies

Brinkmann

Kontermann

2017

mAbs

696

706

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“…The concept of enhancing the internalization and degradation of receptors by promoting the formation of antibody/receptor clusters on the cell surface has been explored fairly extensively (19,20,31,32,(37)(38)(39)(40)(41)(42)(43). The ability of antibodies to promote receptor degradation could result from an increased rate of receptor internalization, a decrease in receptor recycling or both.…”

Section: Discussionmentioning

confidence: 99%

A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models

DaSilva

Yang

Bay

et al. 2020

Clinical Cancer Research

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Purpose: Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody with enhanced efficacy. Experimental Design: Here, we describe the activity of a biparatopic METÂMET antibody that recognizes two distinct epitopes in the MET Sema domain. We use a combination of in vitro assays and tumor models to characterize the effect of our antibody on MET signaling, MET intracellular trafficking, and the growth of METdependent cells/tumors. Results: In MET-driven tumor models, our biparatopic antibody exhibits significantly better activity than either of the parental antibodies or the mixture of the two parental antibodies and outperforms several clinical-stage MET antibodies. Mechanistically, the biparatopic antibody inhibits MET recycling, thereby promoting lysosomal trafficking and degradation of MET. In contrast to the parental antibodies, the biparatopic antibody fails to activate METdependent biological responses, consistent with the observation that it recycles inefficiently and induces very transient downstream signaling. Conclusions: Our results provide strong support for the notion that biparatopic antibodies are a promising therapeutic modality, potentially having greater efficacy than that predicted from the properties of the parental antibodies.

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“…It inhibits the autophosphorylation of EGFR, blocking downstream signaling transduction pathways, and inhibits signal transmission of cell mitosis, which is activated by growth factor and prevents tumor cell proliferation [ 15 ]. In addition, the combination of C225 and EGFR can also induce the engagement of receptors in dimerization, internalization and down-regulation [ 16 ]. C225 can inhibit the progression of the cell cycle from the G1 stage to S stage, induce apoptosis of tumor cells, inhibit tumor angiogenesis and inhibit the invasion and metastasis of tumors by a variety of activators [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma

Zhong

et al. 2018

PLoS ONE

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ObjectiveTo study the characterization of Fe3O4@Au-C225 composite targeted MNPs.MethodsFe3O4@Au-C225 was prepared by the absorption method. The immunosorbent assay was used to evaluate its absorption efficiency at C225 Fc. ZETA SIZER3000 laser particle size analyzer, ultraviolet photometer and its characteristics were analyzed by VSM. the targeting effect of Fe3O4@Au-C225 composite targeted MNPs on U251 cells in vitro were detected by 7.0 Tesla Micro-MR; and subcutaneous transplanted human glioma in nude mice were performed the targeting effect in vivo after tail vein injection of Fe3O4@Au-C225 composite targeted MNPs by MRI.ResultsThe self-prepared Fe3O4@Au composite MNPs can adsorb C225 with high efficiency of adsorption so that Fe3O4@Au-C225 composite targeted MNPs were prepared successfully. Fe3O4@Au-C225 composite targeted MNPs favorably targeted human glioma cell line U251 in vitro; Fe3O4@Au-C225 composite targeted MNPs have good targeting ability to xenografted glioma on nude mice in vivo, and can be traced by MRI.ConclusionThe Fe3O4@Au-C225 composite targeted MNPs have the potential to be used as a tracer for glioma in vivo.

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Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule

Cited by 19 publications

References 19 publications

The making of bispecific antibodies

The making of bispecific antibodies

A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma

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