Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

Abstract

The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model.

DNA Electrostatics: From Theory to Application

“…However, there is yet another aspect of this interaction that can be used not only for DNA detection, but also for the character-ization of biomolecules and molecular interactions. [62] It consists of the alternation of applied potential with respect to the pzc that results in conformational switching of the tethered DNA towards and away from the electrode surface, with a certain amplitude and frequency. [39,63] The extent of the manipulation of DNA depends on the relation between the statistical gyration due to the thermal agitation and the total electrostatic interactions.…”

DARPin_9-29-Targeted Gold Nanorods Selectively Suppress HER2-Positive Tumor Growth in Mice

“…Trastuzumab, a HER2specific monoclonal antibody, has been used in clinical practice to treat HER2-positive breast cancer for about 20 years [7][8][9][10][11]. Designed ankyrin repeat proteins (DARPins), which are characterized by high-affinity interaction with different epitopes of HER2, have also been shown to specifically target HER2-positive cells [12][13][14][15][16][17][18]. Conjugates of DARPins with gold nanostructures have been specifically delivered to HER2-positive cells and the conjugate-targeted cells selectively eradicated by near-infrared (NIR) photothermal therapy [19,20].…”

Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

“…However, there are still some ineluctable deficiencies such as large size, complicated fabrication, unspecific conjugate site, and poor tissue penetration which may influence somewhat the therapeutic efficiency of ADC drugs [ 7 – 9 ]. To circumvent the limitations, various smaller protein fragments such as monobodies [ 10 ], anticalins [ 11 ], DARPins (designed ankyrin repeat proteins) [ 12 ], and nanobodies [ 13 ] have been developed as alternative drug carriers.…”