Phase I study of the anti-CD74 monoclonal antibody milatuzumab (hLL1) in patients with previously treated B-cell lymphomas

Abstract

Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included four planned dose levels (1.5, 4, 6 and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly related toxicities were infusion reaction, anemia, lymphopenia, neutropenia and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2 and 4, respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ∼2 h. In seven patients, In-111 imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.

Keywords: Antibody-based immunotherapy; immunotherapy; lymphoid leukemia; lymphoma and Hodgkin disease.

Figure 1

Pharmacokinetics. A representative example of the pharmacokinetic profile of milatuzumab in a patient with chronic lymphocytic leukemia treated daily (Monday-Friday) for 10 doses at 4 mg/kg. On day 1, plasma samples were collected prior to the infusion, 2 hours from the start of the infusion (30 minutes post-infusion; i.e., infusion time was 90 minutes), and at 1, 2, and 4 hours post-infusion. The Cmax was seen in the 30 minute post-infusion sample. Additional PK samples were taken pre-infusion and 30 minutes following infusion on days 2–10 as well as days 14, 15, 16, and 18.

Figure 2

Biodistribution. Whole body gamma camera images from a patient with CLL and thoracic/abdominal adenopathy treated at dose level 2. In-111-DOTA-hLL1 IgG (~2 mg, 5.0 mCi) was injected 30 minutes after termination of the infusion of the total prescribed dose of unlabeled milatuzumab. The anterior/posterior images were taken 2 hours post infusion on day 6 (left two images) and day 10 (right two images).