A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505 0 s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months.Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206).

Eviction from the sanctuary: Development of targeted therapy against cell adhesion molecules in acute lymphoblastic leukemia

“…A phase 1 dose-escalation study with BI-505 is completed, and it is ready for entering the next phase of clinical trials (49) (Table 5). Thalidomide and its analogue lenalidomide are immunomodulators that function as anti-TNFα agents, via the regulation of cell surface expression of key adhesion molecules like ICAM-1, VCAM-1, E-selectin and L-selectin thereby decreasing cell-cell interaction between T-ALL cells and umbilical vein endothelial cells (50,51).…”

Advances and practical use of monoclonal antibodies in multiple myeloma therapy

“…[3][4][5][6][7] Other mAbs directed against MM cellular antigens that have demonstrated at least stable disease include those directed against CD138 (BT062), CD54/ICAM-1 (BI-505), and CD74 (milatuzumab). [8][9][10] The development of therapeutic mAbs for the treatment of MM has also been directed against growth factors and their receptors (eg, interleukin-6, interleukin-6 receptor, insulin-like growth factor-1 or -2, vascular endothelial growth factor, and B-cell activating factor). Antibodies that augment the host immune response through immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and PD ligand 1 (PD-L1) are also in development.…”

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

“…Increased ICAM-1 expression levels have been observed in multiple myeloma (15) and across many disparate carcinomas including breast (16), pancreas (17), and gastric (18) tumors, and are correlated with tumor progression and metastatic capability (19). Moreover, clinical trials support the safety and tolerability of targeting ICAM-1 using monoclonal antibodies (20–24). Previous studies have shown that ICAM-1 expression is highly correlated with both the malignancy and metastatic status of thyroid tumors, as well as the V600E BRAF (BRAF V600E ) mutation (25, 26).…”