Fc Engineering for Developing Therapeutic Bispecific Antibodies and Novel Scaffolds

Abstract

Therapeutic monoclonal antibodies have become molecules of choice to treat autoimmune disorders, inflammatory diseases, and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (T cell, natural killer cell, or macrophage cell) toward target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas to antibody fragments. Impressively, antibody fragments such as bispecific T-cell engager, bispecific killer cell engager, trispecific killer cell engager, tandem diabody, and dual-affinity-retargeting are showing exciting results in terms of recruiting and activating self-immune effector cells to target and lyse tumor cells. Promisingly, crystallizable fragment (Fc) antigen-binding fragment and monomeric antibody or half antibody may be particularly advantageous to target solid tumors owing to their small size and thus good tissue penetration potential while, on the other hand, keeping Fc-related effector functions such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis, and extended serum half-life via interaction with neonatal Fc receptor. This review, therefore, focuses on the progress of Fc engineering in generating bispecific molecules and on the use of small antibody fragment as scaffolds for therapeutic development.

Recombinant Antibodies to Arm Cytotoxic Lymphocytes in Cancer Immunotherapy

“…To increase the binding affinity to CD16A and to allow for CD16A binding independent of patient genotype, a variety of different antibody formats have been developed [66,67,68]. These combine binding domains and, hence, different functionalities in one antibody molecule.…”

“…Adopting a different strategy, two or more ABDs can be genetically fused to a ‘stable' scaffold allowing further diversity of bispecific molecules. Examples are Fc- or IgG-based bispecific antibody molecules [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97], which have recently entered clinical trials as T-cell recruiters [98]. …”

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

“…Figure 1 shows the basic Monoclonal antibodies (mAbs) have advantages over traditional chemotherapy in that (1) mAbs can bind target antigen speciically and thus reduce of-target side efects associated with traditional chemotherapy; (2) through Fc neonatal receptor (FcRn) recycling mechanism, mAbs have long serum half-life (ranges in days to weeks) when compared to chemotherapy (ranges in minutes to hours); (3) mAbs can recruit efectors for antibodydependent cell-mediated phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) through its Fc region, which functions are missing in chemotherapy [3]. By 2015, more than 60 monoclonal antibodies (mAbs) have been approved by the United States Food and Drug Administration to treat cancer, autoimmune disorders, and infections [4].…”

Pharmacokinetics, Pharmacodynamics, Immunogenicity, Safety, and Tolerability of JNJ‐61178104, a Novel Tumor Necrosis Factor‐Alpha and Interleukin‐17A Bispecific Antibody, in Healthy Subjects

“…10,11 A new generation of biologic therapeutics is being developed on "alternative scaffolds" and mAb-like molecules with the potential to neutralize activities of more than one disease mediator. 10,[12][13][14][15] Expanding responder population and achieving better and long-lasting efficacy with a favorable safety profile are the main goals for these new therapeutic approaches. 10,16,17 Tumor necrosis factor alpha (TNFα) and interleukin (IL)-17A are 2 pleiotropic inflammatory mediators with distinct structure, and are both elevated in patients with arthritis.…”