Antitumor Immunity: Easy as 1, 2, 3 with Monoclonal Bispecific Trifunctional Antibodies?

Abstract

Monoclonal antibodies occupy an increasing niche in the arsenal available to treat cancer. Several developments have rendered this the fastest growing sector in the pharmaceutical industry. Traditionally, antibodies were developed to block key signaling molecules implicated in tumor progression. However, antibodies also recruit additional immune effector mechanisms against tumors, a property that may be exploited for clinical benefit. Bispecific antibodies represent one such strategy in which elements derived from two monoclonal antibodies are incorporated into a single molecular species. Commonly, the bispecific approach is used to achieve simultaneous cross-linking of CD3 and a tumor antigen such as epithelial cell adhesion molecule (EpCAM), thereby recruiting T-cell activation to the tumor cell surface. A further sophistication involves the engineering of trifunctional derivatives such as the clinically approved agent, catumaxomab. Catumaxomab has antigen-binding arms that engage CD3 and EpCAM and a constant domain that recruits Fc receptor-bearing cells, notably monocytes, dendritic cells, and natural killer cells. Owing to this triangular binding capability, catumaxomab can activate both innate and adaptive immune effector mechanisms in addition to promoting immunologic memory. Recent data indicate that this agent can also promote immunogenic cell death, particularly when used in combination with selected chemotherapeutic agents such as oxaliplatin. Cancer Res; 73(18); 5613-7. Ó2013 AACR.

Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system

“…6 The effector functions include antibody-dependent cellmediated cytotoxicity, antibodydependent cellular phagocytosis and complement-dependent cytotoxicity, and are only achievable via interactions between glycosylated Fc and Fc receptors on the effector cells. 65,66 As an E. coli-based cell-free expression system, the Xpress CF platform produces KIH molecules that are aglycosylated and therefore lack effector function.…”

“…5,6 It is produced from a mouse/rat quadroma (hybrid hybridoma) cell, in theory resulting in 12.5% of the total products possessing the desired dual specificity, though preferential pairing between intra-species HC and LC would most likely give rise to a higher amount of bispecific IgG with correct assembly. 3 Such a prodigal process can be largely improved by expression and purification of individual antibodies followed by chemical coupling of 2 IgGs (IgG 2 ) or Fab fragments (F(ab') 2 ).…”

“…28 Because of their unique structural features, the more compact Diabody is often employed as a diagnostic tool or drug delivery vehicle, 29 while BiTEs are generally developed as anti-cancer therapeutics to co-localize T cells and tumor cells to form immunologic synapses and therefore trigger tumor cell cytotoxicity. 6,28 One of the caveats of this category, especially for the BiTE, is also its size (50 kDa), which necessitates continuous intravenous administration to overcome the quick renal serum clearance. 28 As such, different fusion techniques have been explored to extend serum half-life.…”

Effective Cancer Immunotherapy – Are We There Yet?

“…While several of the mAbs approved for clinical use are either chimeric or humanized mAbs, the majority of antibodies currently in various phases of development have fully human peptide sequences. 9 Monoclonal antibodies are thought to function in several ways. MAb directed against cell surface targets (e.g.…”

Specificity Delivers: Therapeutic Role of Tumor Antigen-Specific Antibodies in Pancreatic Cancer

“…It was also able to enhance effector cytokine production and extend the contact time between the T cells and the cancer cells in vivo and in vitro 146, 147 . Catumaxomab has received approval in Europe for use in the treatment of malignant ascites in EpCAM-expressing cancer patients 148, 149 . A multicenter, phase I/II trial testing catumaxomab for treatment of peritoneal carcinomatosis in cancer patients, including PDA, has produced favorable clinical outcomes and safety profile 150 .…”