Affibody-Derived Drug Conjugates Targeting HER2: Effect of Drug Load on Cytotoxicity and Biodistribution.

Published on Mar 23, 2021in Pharmaceutics4.421
· DOI :10.3390/PHARMACEUTICS13030430
Haozhong Ding3
Estimated H-index: 3
Tianqi Xu2
Estimated H-index: 2
+ 5 AuthorsAnzhelika Vorobyeva8
Estimated H-index: 8
#1Mahendra Deonarain (Imperial College London)H-Index: 19
#2Gokhan Yahioglu (Imperial College London)H-Index: 22
3 CitationsSource
#1Tianqi XuH-Index: 2
#2Haozhong DingH-Index: 3
Last. Torbjörn GräslundH-Index: 21
view all 7 authors...
The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, ZHER2:2891, fused with a plasma ...
1 CitationsSource
#1Haozhong Ding (KTH: Royal Institute of Technology)H-Index: 3
#2Mohamed Altai (Uppsala University)H-Index: 18
Last. Anna Orlova (Uppsala University)H-Index: 43
view all 7 authors...
Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previo...
3 CitationsSource
#1Hao Liu (KTH: Royal Institute of Technology)H-Index: 4
#1Hao Liu (KTH: Royal Institute of Technology)H-Index: 23
Last. Torbjörn Gräslund (KTH: Royal Institute of Technology)H-Index: 21
view all 9 authors...
Potent and specific fusion toxins consisting of a HER2-binding ABD-derived affinity protein (ADAPT), fused to truncated versions of Pseudomonas exotoxin A
5 CitationsSource
#1Mohamed Altai (Uppsala University)H-Index: 18
#2Hao Liu (KTH: Royal Institute of Technology)H-Index: 4
Last. Torbjörn Gräslund (KTH: Royal Institute of Technology)H-Index: 21
view all 8 authors...
Abstract Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, ZHER2:2891, conjugated with the cytotoxic mayt...
17 CitationsSource
#1Nirnoy Dan (UTHSC: University of Tennessee Health Science Center)H-Index: 6
#2Saini Setua (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Subhash C. Chauhan (UTHSC: University of Tennessee Health Science Center)H-Index: 43
view all 7 authors...
Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal t...
82 CitationsSource
#1Xiuxia Sun (ImmunoGen, Inc.)H-Index: 6
#2Jose F. Ponte (ImmunoGen, Inc.)H-Index: 10
Last. John M. LambertH-Index: 42
view all 21 authors...
Antibody–drug conjugates (ADCs) are being actively pursued as a treatment option for cancer following the regulatory approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). ADCs consist of a cytotoxic agent conjugated to a targeting antibody through a linker. The two approved ADCs (and most ADCs now in the clinic that use a microtubule disrupting agent as the payload) are heterogeneous conjugates with an average drug-to-antibody ratio (DAR) of 3–4 (potentially ranging...
58 CitationsSource
#1Anna M. Serwotka-Suszczak (UWr: University of Wrocław)H-Index: 2
#2Alicja M. Sochaj-Gregorczyk (UWr: University of Wrocław)H-Index: 3
Last. Jacek Otlewski (UWr: University of Wrocław)H-Index: 38
view all 6 authors...
Antibody-drug conjugates (ADCs) have recently emerged as efficient and selective cancer treatment therapeutics. Currently, alternative forms of drug carriers that can replace monoclonal antibodies are under intensive investigation. Here, a cytotoxic conjugate of an anti-HER2 (Human Epidermal Growth Factor Receptor 2) diaffibody with monomethyl-auristatin E (MMAE) is proposed as a potential anticancer therapeutic. The anti-HER2 diaffibody was based on the ZHER2:4 affibody amino acid sequence. The...
10 CitationsSource
#1Yusuke Ogitani (Daiichi Sankyo)H-Index: 8
#2Tetsuo Aida (Daiichi Sankyo)H-Index: 5
Last. Toshinori Agatsuma (Daiichi Sankyo)H-Index: 11
view all 16 authors...
Purpose: An anti-HER2 antibody–drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed. Experimental Design:In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys an...
175 CitationsSource
#1Anish ThomasH-Index: 35
#2Beverly A. TeicherH-Index: 50
Last. Raffit HassanH-Index: 48
view all 3 authors...
Summary Antibody–drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody–drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. S...
176 CitationsSource
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