Abstract
Purpose
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.
Conclusion
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.
Similar content being viewed by others
Abbreviations
- BCL:
-
B-cell lymphoma
- CalichDMH:
-
N-acetyl gamma calicheamicin dimethyl hydrazide
- CHOP:
-
Cyclophosphamide doxorubicin vincristine prednisone
- CVP:
-
Cyclophosphamide vincristine prednisone
- B-NHL:
-
Non-Hodgkin’s B-cell lymphoma
References
Damle NK (2004) Tumor-targeted chemotherapy with immunoconjugates of calicheamicin. Expert Opin Biol Ther 4:1445–1452
Bross PF, Beitz J, Chen G et al (2001) Gemtuzumab ozogamicin: approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490–1496
Ghobrial I, Witzig T (2004) Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin’s lymphoma. Oncology 18:623–630
DiJoseph JF, Armellino DC, Boghaert E et al (2004) Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B lymphoid malignancies. Blood 103:1807–1814
Zein N, Sinha A, McGahren W, Ellestad G (1988) Calicheamicin γI: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science 240:1198–1201
Hamann PR, Hinman LM, Beyer CF et al (2002) An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconj Chem 13:40–46
DiJoseph JF, Goad ME, Dougher MM et al (2004) Potent and specific anti-tumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin Cancer Res 10:8620–8629
DiJoseph JF, Dougher MM, Kalyandrug LB et al (2006) Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin’s B-cell lymphoma. Clin Cancer Res 12:242–249
Advani A, Gisselbrecht EGC, Rohatiner A et al (2005) Preliminary report of a phase 1 study of CMC-544, an antibody-targeted chemotherapy agent, in patients with B-cell non Hodgkin’s lymphoma (NHL). Blood 106:230a
Fayad L, Patel H, Verhoef G et al (2006) Clinical activity of the immunoconjugate CMC-544 in B-cell malignancies: Preliminary report of the expanded maximum tolerated dose (MTD) cohort of a phase 1 study. Blood 108:766a
Tobinai K, Ogura M, Hatake K et al (2008) Phase I pharmacokinetic study of inotuzumab ozogamicin (CMC-544) as a single agent in Japanese patients with follicular lymphoma pretreated with rituximab. Blood 112:1565
Fayad L, Patel H, Verhoef G et al (2008) Safety, clinical activity of the anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) in combination with rituximab in follicular lymphoma or diffuse large B-cell lymphoma: preliminary report of a phase 1/2 study. Blood 112:266
Fisher RI, Gaynor ER, Dalhberg S et al (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002–1006
McKelevet EM, Gottlieb JA, Wilson HE et al (1976) Hydroxyldaunomycin (adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484–1493
Coiffier B, Lepage E, Briere J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242
DiJoseph JF, Popplewell A, Tickle S et al (2005) Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22. Cancer Immunol Immunother 54:11–24
Mohammad RM, Wall NR, Dutcher JA, Al-Katib AM (2000) The addition of bryostatin 1 to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenografts model. Clin Cancer Res 6:4950–4956
Jenkins JS, Sampson PA (1967) Conversion of cortisone to cortisol and prednisone to prednisolone. Br Med J 2:205–207
Flavell DJ, Boehm DA, Emery L, Noss A, Ramsey A, Flavell SU (1995) Therapy of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19-and anti-CD38-saporin immunotoxins used alone in combination than with either immunotoxin alone. Int J Cancer 62:337–344
Hamann P, Hinman L, Hollander I et al (2002) Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconj Chem 13:47–58
Clavio M, Albarello A, Vignolo L (2007) Adding low-dose gemtuzumab ozogamicin to fludarabine, Aca-C and idarubicin (MY-FLAI) may improve disease-free and overall survival in elderly patients with non-M3 acute myeloid leukemia: results of a prospective, pilot, multi-centre trial and comparison with a historical cohort of patients. Br J Haematol 138:186–195
Burnett AK, Kell WJ, Goldstone AH et al (2006) The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity. Preliminary analysis of 1115 patients in the MRC AML15 trial. Blood 13:8a
Author information
Authors and Affiliations
Corresponding author
Additional information
All authors were employees of Wyeth Research during the conduct of this investigation. CMC-544 is a collaboration product being jointly developed by Wyeth Research and UCB Celltech, Slough, UK.
Rights and permissions
About this article
Cite this article
DiJoseph, J.F., Dougher, M.M., Evans, D.Y. et al. 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. Cancer Chemother Pharmacol 67, 741–749 (2011). https://doi.org/10.1007/s00280-010-1342-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-010-1342-9