RT Journal Article
SR Electronic
T1 Carfilzomib Is Not an Appropriate Payload of Antibody-Drug Conjugates Due to Rapid Inactivation by Lysosomal Enzymes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 884
OP 889
DO 10.1124/dmd.119.086595
VO 47
IS 8
A1 Ma, Yong
A1 Dela Cruz-Chuh, Josefa
A1 Khojasteh, S. Cyrus
A1 Dragovich, Peter S.
A1 Pillow, Thomas H.
A1 Zhang, Donglu
YR 2019
UL http://dmd.aspetjournals.org/content/47/8/884.abstract
AB Carfilzomib (CFZ) is a proteasome inhibitor used for oncology indications including treating multiple myeloma. CFZ is a potent cytotoxic agent with an IC50 value in the nanomolar range in various cancer cell lines and was considered as a potential payload for antibody drug conjugates (ADCs); however, the conjugated CFZ to anti-CD22 or anti-HER2 antibody totally abolishes the in vitro potency. This was a surprise since with other payloads such as monomethyl auristatin E (MMAE), where potent antiproliferation efficacy was retained as MMAE alone or as a payload in an ADC. Further investigations were conducted using CFZ alone, CFZ with a linker, and CFZ-ADC with tissue matrices including lysosomal enzymes. With CFZ linked to the ADC, cathepsin B (a lysosomal enzyme) was efficient in liberating CFZ from the ADC by cleavage of the valine-citrulline linker. At the same time, the liberated CFZ in the lysosome was inactivated due to further metabolism by lysosomal enzymes. The products from epoxide and amide hydrolysis were identified from these incubations. These results suggested that the CFZ-ADC upon uptake and internalization specifically delivers CFZ payload to the lysosomes, where CFZ was inactivated. On the other hand, CFZ by itself is not as vulnerable and could reach its target. Therefore, lysosomal stability is an important criterion in the selection of a payload for making the next generation of potent ADC therapeutics.