) Our recent in vitro and preclinical studies have shown that certain human mAbs derived from the V4-34 gene are cytotoxic to normal and malignant B lymphocytes. 216, the most cytotoxic of V4-34 derived Ab from our library, has shown minimum toxicity accompanied by significant protection in a human lymphoma models developed in CB17-scid/scid and NOD/LtSz-scid/scid mice. MAb 216 meets all the criteria for an efficacious treatment. Its ligand does not down regulate and is present on majority of B cell lymphomas. It will be associated with minimal toxicity, side effects and immunogenicity. Toxicity is mediated by two independent mechanisms. The first is effector independent, temperature dependent pathway that cross-links the cytoskeletally associated B cell ligand leading to disruption of the cell membrane integrity. The second is the conventional pathway of complement fixation. Toxicity is B cell specific and will not lead to general immune suppression since stem cells are not affected. Finally this human IgM is easy to prepare and use. In this proposal phase I evaluation of human Ab 216 for treatment of recurrent of B cell lymphoma will be undertaken. Twelve patients with relapsed lymphoma who have failed a least one form of therapy will receive escalating doses of 216, with three patients at each dose level. The initial dose will be 50 mgtm2 with subsequent doses escalated as follows: 100 mg/m2, 250 mg/m2 and 400 mg/m2. The pharmacokinetics, toxicity and efficacy of a single injection will be evaluated. Pharmacokinetics of the 216, serum levels and immune response to the injected Ab will be measured. Peripheral blood B cell levels will be monitored. Patients receiving doses of 100 mg/m2 or greater will undergo fine needle lymph node biopsy on day 14 for analysis of Ah penetration. Tumor response will be assessed. Because this therapy may benefit the patient with B cell lymphoma and would have no benefit for other subjects only lymphoma patients will be studied. There will be no control subjects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA085199-01
Application #
6081103
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
Project Start
2000-07-01
Project End
2005-12-31
Budget Start
2000-07-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2000
Total Cost
$79,700
Indirect Cost
Name
Stanford University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305