Lucatumumab Overview

Introduction of Lucatumumab

Lucatumumab (as known as CHIR 12.12 or HCD122) is a human monoclonal antibody (mAb) being investigated for the treatment of various types of cancer like multiple myeloma, non-Hodgkin's or Hodgkin's lymphoma. It is an antagonist to CD40 that was created by scientists at Chiron using Abgenix' XenoMouse transgenic mouse to generate fully human antibodies. It was made part of the collaboration between Chiron and Xoma that the companies commenced in 2004 and Novartis took over the project when it acquired Chiron in 2005. Lucatumumab binds to tumor cells that express CD40 and antagonizes (prevents) CD40 ligand-mediated growth and survival of malignant B cells. Based on preclinical data, lucatumumab also induces antibody-dependent cellular cytotoxicity (ADCC), killing CD40 expressing tumor cells by immune effector cells. This dual mechanism of action makes HCD122 a drug candidate with potential for the treatment of B-cell malignancies.

Mechanism of Action of Lucatumumab

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world and is a disease of older adults. For many years the biology of CLL was thought to be simply due to progressive accumulation of morphologically mature-appearing B lymphocytes in the blood, bone marrow and lymphatic tissues. These malignant lymphocytes typically express receptors to a variety of cytokines or soluble ligands including interleukins and tumor necrosis factor (TNF) family members whose soluble ligand under experimental conditions can disrupt spontaneous apoptosis commonly observed with CLL. CD40 is a type-1 transmembrane protein of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule upon interaction with its ligand CD154 (CD40L). CD40 is expressed on B cells and their progenitors, epithelial and endothelial cells, and many antigen-presenting cells (dendritic cells, activated B lymphocytes, and activated monocytes). In normal B-cells, CD40 ligation promotes activation of both the phosphoinositol (PI) 3-kinase pathway, and nuclear factor κB (NF-κB), thereby disrupting apoptosis; CD40 ligation also promotes activation and proliferation when administered with other cytokines. Similar PI3-kinase and NF-κB activation is observed when CLL cells are treated with CD40L, with several groups demonstrating disruption of both spontaneous and drug induced apoptosis. Disrupting the CD40L–CD40 signaling axis represents a potential therapeutic target for the treatment of CLL and other B-cell malignancies dependent upon this pathway.

Lucatumumab is one such potential therapeutic to target the CD40L–CD40 pathway. Lucatumumab is a fully human, recombinant monoclonal antibody of the immunoglobulin G1 (IgG1) isotype targeting human CD40. Preclinically, lucatumumab is a potent antagonist that blocks signaling by CD40L. It binds to CD40 molecules with high affinity and has a slow off-rate. In vitro, lucatumumab inhibits CD40L-mediated proliferation of normal B cells, CLL cells and non-Hodgkin lymphoma (NHL) cells. In the absence of CD40L, lucatumumab does not stimulate proliferation of either normal B cells or malignant B cells from patients with CLL or NHL. Lucatumumab also has the capacity to mediate killing and clearance of tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and opsonization. In vitro studies demonstrate that lucatumumab is not internalized after binding, remaining available on the cell surface to bind effector cells and mediate cell lysis via ADCC. Additionally, data from human lymphoma and myeloma xenograft models suggest a potential role for lucatumumab in the treatment of lymphoid malignancies. Studies with primary CLL cells demonstrated that lucatumumab could inhibit CD40L-induced protection from apoptosis. Furthermore, lucatumumab is also a potent mediator of ADCC against CLL cells, and is more potent than rituximab.

Fig 1. Mechanism of Action of Lucatumumab

What We Provide

Therapeutic Antibody

Lucatumumab

We provide high-quality Lucatumumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

For research use only. Not intended for any clinical use.