Abstract
Overexpression of insulin growth factor receptor type 1 (IGF-1R) is observed in many cancers. Antibody drug conjugates (ADCs) with PEGylated maytansine (PEG6-DM1) show promise in vitro. We developed PEG6-DM1 ADCs with low and high drug to antibody ratios (DAR) using an anti-IGF-1R antibody cixutumumab (IMC-A12). Conjugates with low (cixutumumab-PEG6-DM1-Low) and high (cixutumumab-PEG6-DM1-High) DAR as 3.4 and 7.2, respectively, were generated. QC was performed by UV spectrophotometry, HPLC, bioanalyzer, and biolayer-interferometry. We compared the in vitro binding and internalization rates of the ADCs in IGF-1R-positive MCF-7/Her18 cells. We radiolabeled the ADCs with 111In and used microSPECT/CT imaging and ex vivo biodistribution to understand their in vivo behavior in MCF-7/Her18 xenograft mice. The therapeutic potential of the ADC was studied in vitro and in mouse xenograft. Internalization rates of all ADCs was high and increased over 48 h and EC50 was in the low nanomolar range. MicroSPECT/CT imaging and ex vivo biodistribution showed significantly lower tumor uptake of 111In-cixutumumab-PEG6-DM1-High compared to 111In-cixutumumab-PEG6-DM1-Low and 111In-cixutumumab. Cixutumumab-PEG6-DM1-Low significantly prolonged the survival of mice bearing MCF-7/Her18 xenograft compared with cixutumumab, cixutumumab-PEG6-DM1-High, or the PBS control group. Cixutumumab-PEG6-DM1-Low ADC was more effective. The study highlights the potential utility of cixutumumab-ADCs as theranostics against IGF-1R positive cancers.
Highlights
Insulin growth factor receptor type 1 (IGF-1R) plays a key role in normal growth and development
In trastuzumab-DMI (T-DM1; K adcyla®), the antibody is conjugated to DM1 via a non-cleavable linker N-maleimidomethyl cyclohexane-1-carboxylate (MCC)
Recent data show that Antibody drug conjugates (ADCs) developed using PEG-DM1 are more potent, and can be loaded with a high drug to antibody ratio (DAR) than those developed with non-PEGylated DM1
Summary
Insulin growth factor receptor type 1 (IGF-1R) plays a key role in normal growth and development. Altered expression of IGF-1 pathway is implicated in the development and maintenance of malignant phenotypes in many primary cancers (such as lung, colorectal, pancreatic, breast, and colon cancers and glioblastomas) and their metastases, suggesting that imaging and therapeutic agents targeting IGF-1R receptor have a potential for diagnosis and therapy[1,2,3,4] In addition to their role in these cancers, a cross-talk between IGF-1R and other growth factor receptors, notably epidermal growth factor receptors (HER family) has been implicated in the development of resistance to targeted therapies[4,5,6,7]. Factors responsible for resistance include low antigen expression, receptor down-regulation, inefficient lysosomal degradation of T-DM1 and most notably the expression of drug efflux pump multidrug resistant gene (MDR1). Small molecules such as DM1 are substrates for MDR1 and readily pumped out of the cell via P gP16–18. We have evaluated the in vivo efficacy of the ADCs in mice bearing IGF-1R positive breast cancer xenograft
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