Abstract
Antibody drug conjugates (ADCs) are monoclonal antibodies designed to deliver a cytotoxic drug selectively to antigen expressing cells. Several components of an ADC including the selection of the antibody, the linker, the cytotoxic drug payload and the site of attachment used to attach the drug to the antibody are critical to the activity and development of the ADC.The cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues. This results in ADCs that have a heterogeneous number of drugs per antibody. The number of drugs per antibody commonly referred to as the drug to antibody ratio (DAR), can vary between 0 and 8 drugs for a IgG1 antibody. Antibodies with 0 drugs are ineffective and compete with the ADC for binding to the antigen expressing cells. Antibodies with 8 drugs per antibody have reduced in vivo stability, which may contribute to non target related toxicities.In these studies we incorporated a non-natural amino acid, para acetyl phenylalanine, at two unique sites within an antibody against Her2/neu. We covalently attached a cytotoxic drug to these sites to form an ADC which contains two drugs per antibody.We report the results from the first direct preclinical comparison of a site specific non-natural amino acid anti-Her2 ADC and a cysteine conjugated anti-Her2 ADC. We report that the site specific non-natural amino acid anti-Her2 ADCs have superior in vitro serum stability and preclinical toxicology profile in rats as compared to the cysteine conjugated anti-Her2 ADCs. We also demonstrate that the site specific non-natural amino acid anti-Her2 ADCs maintain their in vitro potency and in vivo efficacy against Her2 expressing human tumor cell lines. Our data suggests that site specific non-natural amino acid ADCs may have a superior therapeutic window than cysteine conjugated ADCs.
Highlights
Antibody-drug conjugates (ADCs) are antibodies engineered to deliver a cytotoxic drug directly to tumor cells expressing the appropriate cell surface antigen
HerceptinH (Trastuzumab) is a humanized IgG1 monoclonal antibody that binds to human Her2/neu, which is highly expressed on breast, ovarian and gastric cancers [2]
A shift in the molecular weights of the heavy chain of the anti-Her2 ADCs is observed when compared against the molecular weight of the unconjugated non-natural amino acid containing anti-Her2 antibody
Summary
Antibody-drug conjugates (ADCs) are antibodies engineered to deliver a cytotoxic drug directly to tumor cells expressing the appropriate cell surface antigen. The selective and stable delivery of the cytotoxic drug to the tumor and not to the normal tissues should reduce the toxicities associated with cytotoxic drug and potentially improve the therapeutic index of the ADC. Successful development of an ADC involves optimization of several components including the antibody, the potency of the cytotoxic drug, the stability of the linker and the site of drug-linker attachment [1]. In order to begin our evaluation, we selected the clinically validated antibody, Herceptin, for our studies. Amplification of Her2/neu results in increased Her2/neu expression and is associated with a poor prognosis [2,3]
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