Preclinical anti-tumor activity of antibody-targeted chemotherapy with CMC-544 (inotuzumab ozogamicin), a CD22-specific immunoconjugate of calicheamicin, compared with non-targeted combination chemotherapy with CVP or CHOP.
OBJECTIVE
CMC-544 (inotuzumab ozogamicin) is a CD22-specific immunoconjugate of calicheamicin currently being evaluated in patients with non-Hodgkin's B-cell lymphoma (BCL). CHOP and CVP represent untargeted combination chemotherapy comprised of cyclophosphamide, vincristine and prednisone with or without doxorubicin, commonly used in the treatment of NHL. Here, we describe anti-tumor efficacy of CMC-544, CHOP or CVP against human BCL xenografts.


METHODS
In vitro, human BCLs were cultured with CMC-544 or individual constituents of CHOP for inhibition of their growth. In vivo, immunocompromised mice with established BCL xenografts were administered CHOP, CVP or CMC-544 to monitor their survival and BCL growth.


RESULTS
In vitro, CMC-544 was more potent in causing growth inhibition of various BCL than cyclophosphamide, doxorubicin, vincristine or dexamethasone. In vivo, treatment with CHOP or CVP inhibited growth of BCL xenografts for up to 40 days after which BCL relapsed. Tumor growth inhibition by CMC-544 (>100 days) lasted longer than that by CHOP or CVP. BCL xenografts that relapsed after the treatment with CHOP or CVP were far less responsive to CHOP or CVP re-treatment but regressed upon subsequent treatment with CMC-544. CVP could be co-administered with suboptimal doses of CMC-544, while CHOP could be administered on alternant days with CMC-544 to cause enhanced regression of established BCL xenografts.


CONCLUSIONS
Preclinically, CMC-544 provides greater therapeutic benefit than CVP or CHOP against BCL xenografts. CMC-544 may also be co-administered with standard chemotherapeutic regimens in the treatment of B-NHL for superior anti-tumor activity.
DiJoseph
John F
JF
Oncology Discovery, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. dijosej@wyeth.com
Dougher
Maureen M
MM
Evans
Deborah Y
DY
Zhou
Bin-Bing
BB
Damle
Nitin K
NK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology; D012008:Recurrence; D013534:Survival; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000080045:Inotuzumab Ozogamicin; D011241:Prednisone