Initial Trials of Anti-CD80 Monoclonal Antibody (Galiximab) Therapy for Patients with Relapsed or Refractory Follicular Lymphoma
2003; Elsevier BV; Volume: 3; Issue: 4 Linguagem: Inglês
10.3816/clm.2003.n.008
ISSN2331-4486
AutoresAnas Younes, Kandasamy Hariharan, R. S. Allen, Bryan R. Leigh,
Tópico(s)Immunotherapy and Immune Responses
Resumo257 Rationale The costimulatory molecule, CD80 (B7-1), is well known for its role in the regulation of T-cell function.1 Recent evidence suggests that CD80 also plays a role in the regulation and activation of normal and malignant B cells.2,3 CD80 is expressed on a variety of B-cell lymphomas, including follicular, diffuse, small noncleaved, mantle cell, small lymphocytic, and other subtypes.4,5 Crosslinking of CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation and to upregulate proapoptotic molecules.2 Taken together, these observations constitute rationale for the development of an anti-CD80 therapy for B-cell lymphoma. Galiximab (IDEC-114) is a Primatized® anti-CD80, immunoglobulin G1 lambda monoclonal antibody with human constant regions and primate (cynomolgus macaque) variable regions.6 Galiximab blocks binding of CD80 with CD28 but not with CTLA-4. Preclinical studies explored the potential of galiximab as a targeted therapy for lymphoma, as a single agent, or in combination with rituximab, an anti-CD20 monoclonal antibody.7 CD80 expression was confirmed on several lymphoma cell lines and on biopsy specimens from patients with low-grade, intermediate-grade, and high-grade lymphoma, using immunohistochemistry and flow cytometry. CD80 expression on 12 biopsy specimens of follicular small-cleaved lowgrade non-Hodgkin’s lymphoma (NHL) is shown in Table 1. The mechanism of action of galiximab was investigated using in vitro assays. These studies demonstrated that both galiximab and rituximab lysed cells via antibody-dependent cellular cytotoxicity mechanisms (Figure 1). Animal studies explored the in vivo effects of galiximab. In a model of severe combined immunodeficient mice implanted with human lymphoma xenografts, mice treated with galiximab had a significantly longer disease-free survival (DFS) compared to untreated control mice. Similarly, mice treated with galiximab and rituximab had significantly longer DFS compared to mice treated with rituximab alone. In addition, no adverse reactions were observed in primate toxicology studies in which animals received up to 30 mg/kg (≈ 1200 mg/m2) for 5 months (ie, weekly for 5 weeks and then monthly for 5 months). In humans with moderate to severe plaque psoriasis, approximately 300 patients received up to 15 mg/kg (≈ 600 mg/m2) galiximab in single-dose8 and multiple-dose9 clinical trials. Galiximab was infused over 1 hour in an outpatient setting. The 1M. D. Anderson Cancer Center, Houston,TX 2IDEC Pharmaceuticals Corporation, San Diego, CA
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