Phase IA/II, multicentre, open‐label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non‐Hodgkin or Hodgkin lymphoma

Abstract

; San Diego, CA: abstract 3702. SummaryDespite advancements in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8-week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa-associated lymphatic tissue (MZL/MALT) was 33Á3% and 42Á9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.

LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

“…A CD40-blocking Ab is already being tested in human subjects for potential use as an immunosuppressive agent to prevent organ rejection in transplant patients. Although CD40L-blocking Abs proved to be toxic in humans because of unexpected thromboembolic effects (due to CD40L expression on platelets), to date, CD40 receptor-blocking Abs have not been found to have similar toxicity in humans (52,53). Nevertheless, since CD40-blocking Abs are predicted to be immunosuppressive, they might be most useful for inhibiting the development of EBV-induced lymphomas in organ transplant patients, while simultaneously preventing organ rejection.…”

ATVB Distinguished Scientist Award

“…192, 193 Also, agonistic or antagonistic anti-CD40 antibodies failed in diverse clinical disorders as the treatment was not efficient, or side effects including thrombocytopenia, neutropenia, and pleural effusion led to the discontinuation of trials. 194–196 An alternative therapeutic strategy harnesses interactions of CD40L with Mac-1, also known as CD11b/CD18 integrin, which is abundantly expressed of neutrophils, NK cells, monocytes, and macrophages. 197 The intraperitoneal application of a small peptide prevented interaction of CD40L with Mac-1 and reduced atherosclerotic burden in Ldlr −/− mice, potentially by reducing leukocyte recruitment to the inflammatory site.…”

Obinutuzumab For The Treatment Of Indolent Lymphoma

“…Anti-CD19 monoclonal antibodies show efficacy when they are conjugated to either a cytotoxic agent, such as in SAR3419 [38,39], or another antibody fragment, such as in the bispecific T-cell-engaging antibody blinatumomab [40]. Otlertuzumab as anti-CD37 monoclonal antibody [41,42] and lucatumumab as anti-CD40 monoclonal antibody showed modest clinical activity [43,44]. These antibodies remain investigational and CD20 antigen still remains by far the most successful target up to now.…”