Superior antitumor activity of SAR3419 to rituximab in xenograft models for non-Hodgkin's lymphoma.
OBJECTIVE
To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N(2)'-deacetyl-N(2)'-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma.


METHODS
Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency.


RESULTS
Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristine-prednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma.


CONCLUSIONS
Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.
Al-Katib
Ayad M
AM
Lymphoma Research Laboratory, Wayne State University School of Medicine, Detroit, Michigan 48202, USA. alkatib@med.wayne.edu
Aboukameel
Amro
A
Mohammad
Ramzi
R
Bissery
Marie-Christine
MC
Zuany-Amorim
Claudia
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D011241:Prednisone / Q000627:therapeutic use; D000069283:Rituximab; D014750:Vincristine / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D007155:Immunologic Factors; D008453:Maytansine; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone