PT  - JOURNAL ARTICLE
AU  - Yong Ma
AU  - Josefa Dela Cruz-Chuh
AU  - S. Cyrus Khojasteh
AU  - Peter S. Dragovich
AU  - Thomas H. Pillow
AU  - Donglu Zhang
TI  - Carfilzomib Is Not an Appropriate Payload of Antibody-Drug Conjugates Due to Rapid Inactivation by Lysosomal Enzymes
AID  - 10.1124/dmd.119.086595
DP  - 2019 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 884--889
VI  - 47
IP  - 8
4099  - http://dmd.aspetjournals.org/content/47/8/884.short
4100  - http://dmd.aspetjournals.org/content/47/8/884.full
SO  - Drug Metab Dispos2019 Aug 01; 47
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.