Engineering therapeutic monoclonal antibodies

Abstract

During last two decades, the chimerization and humanization of monoclonal antibodies (mAbs) have led to the approval of several for the treatment of cancer, autoimmune diseases, and transplant rejection. Additional approaches have been used to further improve their in vivo activity. These include combining them with other modalities such as chemotherapy and redesigning them for improved pharmacokinetics, effector function, and signaling activity. The latter has taken advantage of new insights emerging from an increased understanding of the cellular and molecular mechanisms that are involved in the interaction of immunoglobulin G with Fc receptors and complement as well as the negative signaling resulting from the hypercrosslinking of their target antigens. Hence, mAbs have been redesigned to include mutations in their Fc portions, thereby endowing them with enhanced or decreased effector functions and more desirable pharmacokinetic properties. Their valency has been increased to decrease their dissociation rate from cells and enhance their ability to induce apoptosis and cell cycle arrest. In this review we discuss these redesigned mAbs and current data concerning their evaluation both in vitro and in vivo.

Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β Activity

“…S1-S4. 1 To whom correspondence should be addressed: 2910 Seventh St., Berkeley, CA 94710. antibody should not interfere with neutralization of IL-1␤ by soluble receptors, clearance of IL-1␤ by receptor-mediated pathways, IL-1␣ signaling, or IL-1Ra activity. We propose that using an antibody to selectively reduce the affinity of a ligand for its signaling receptor will have the effect of reducing signaling output by reducing receptor occupancy by ligand.…”

“…Recombinant monoclonal antibodies have emerged as powerful targeted therapies for severe diseases (1,2), often acting by blocking activity of dysregulated cellular pathways. However, most pathways that have been linked to disease when abnormally activated have important roles in healthy tissues.…”

Lonely killers

“…2,3,15 For instance, from the above mentioned mAbs that bind to cells, rituximab is known to exert all of them. 16,17 Although still the subject of some controversy, methods to measure and characterize the different types of cell death are being unified.…”

Practical considerations for nonclinical safety evaluation of therapeutic monoclonal antibodies

“…[4][5][6][7] More recently, fully human antibodies are also being developed that are generated using transgenic animals or display technologies. [8][9][10] In addition to favorably altering binding affinities, customized mAbs that have enhanced effector function e.g., antibodydependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are even possible. To improve efficacy and increase the chance for clinical success, mAbs that have been modified to alter glycosylation, target binding affinity and half-life are now increasingly considered for clinical development.…”

“…To improve efficacy and increase the chance for clinical success, mAbs that have been modified to alter glycosylation, target binding affinity and half-life are now increasingly considered for clinical development. 2,3,10 Concurrently, the technology for the generation of high-titer mAb-producing cell lines from mammalian and non-mammalian origins has also evolved. 11,12 Thus, a thorough nonclinical safety evaluation of these mAbs is very important due to the increasing complexity of antibody engineering aspects and the variability induced by the diversity of recombinant production cell systems for generation of antibodies.…”