In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 3091-3091
Abstract:
3091 Background: CD74 is commonly considered to be an antigen present in hematopoietic cancers, but it is also expressed in a number of solid tumors. The humanized anti-CD74 antibody, milatuzumab (hLL1), was previously shown to have exquisite internalization properties, making it an attractive carrier for drug delivery. In this study, we evaluated hLL1 conjugates of a potent topo I inhibitor, SN-38, for treating solid tumors. Methods: Two hLL1-SN-38 conjugates, possessing either a pH-sensitive linker (‘CL2A’ form) or a cathepsin-B-cleavable linker ("CL2E" form), were examined. In vitro analyses were carried out in the A-375 human melanoma cell line, and therapy experiments were performed in female athymic nude mice bearing established s.c. A-375 or s.c. human pancreatic adenocarcinoma (Capan-1) xenografts using specified doses (i.p.) at a twice weekly × 4 wks schedule; animals were sacrificed when tumor volumes (TVs) reached 1 cm 3 . Results: Both A-375 and Capan-1 cell lines tested positive for CD74 expression by IHC. In vitro, both SN-38 derivatives liberated free drug at the same rate when exposed to cathepsin-B at pH 5, while serum stabilities for CL2A and CL2E forms of the conjugates were ~ 1 d and 〉 10 d, respectively. In the A-375 melanoma cell line, IC 50 for the hLL1-SN-38 conjugates of CL2A and CL2E forms were 5 nM and 34 nM, respectively. In the aggressive A-375 s.c. model of melanoma, in nude mice (n =8; TV: 0.23 ± 0.06 cm 3 ) treated with 12.5 mg/kg protein dose (total 1.7 mg/kg SN-38 eq.) of specific or non-specific SN-38 conjugates of CL2A and CL2E forms, only hLL1-CL2A-SN-38 conjugate was efficacious (Log-rank: P 〈 0.009 vs. all controls), with a median survival time of 28 d vs. 10.5 d for untreated. Likewise, in mice bearing Capan-1 xenografts (n = 8-10; TV=0.27 ± 0.05 cm 3 ), two low doses of hLL1-CL2A-SN-38 (12.5 or 5 mg/kg) significantly improved survival in comparison to saline control mice (p 〈 0.035), whereas the CL2E form and a non-specific control demonstrated no efficacy. Conclusions: These results indicate the therapeutic potential of hLL1-CL2A-SN-38 conjugate and the importance of linker chemistry, and encourage additional testing in other CD74-positive solid cancers.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.3091
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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