Affibody-derived drug conjugates : Potent cytotoxic molecules for treatment of HER2 over-expressing tumors

• 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 maytansine derivate MC-DM1, for targeted cancer therapy. ZHER2:2891 was expressed as a monomer (ZHER2:2891), dimer ((ZHER2:2891)2) and dimer with an albumin binding domain (ABD) for half-life extension ((ZHER2:2891)2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (ZHER2:2891)2-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (ZHER2:2891)2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers. 

Ämnesord

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

ADC

Affibody molecule

DM1

HER2

Maytansine

Amino acids

Diseases

Mammals

Molecules

Monoclonal antibodies

Patient treatment

Tumors

Affibody molecules

Clinical evaluation

Molecular signatures

Targeted cancer therapy

Terminal cysteine

Treatment modality

Dimers

(z human epidermal growth factor receptor 2 2891) 2 albumin binding domain iaa conjugate

(z human epidermal growth factor receptor 2 2891) 2 albumin binding domain mc dm1 conjugate

(z human epidermal growth factor receptor 2 2891) 2 mc dm1 conjugate

(z human epidermal growth factor receptor 2 2891) mc dm1 conjugate

(z taq) 2 albumin binding domain mc dm1 conjugate

cysteine

cytotoxic agent

dimer

epidermal growth factor receptor 2

epidermal growth factor receptor kinase inhibitor

monomer

serum albumin

technetium 99m

trastuzumab emtansine

unclassified drug

albumin binding domain

animal experiment

animal model

animal tissue

Article

AU565 cell line

binding affinity

cancer survival

carboxy terminal sequence

controlled study

drug conjugation

drug cytotoxicity

drug dose comparison

drug efficacy

drug half life

drug potency

drug specificity

drug targeting

drug tolerability

female

human

human tissue

IC50

in vitro study

isotope labeling

kidney tissue

liver tissue

MCF-7 cell line

molecularly targeted therapy

mouse

nonhuman

ovary carcinoma

priority journal

protein expression

protein structure

SK-BR-3 cell line

SK-OV-3 cell line

tissue distribution

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)