To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development.

Bispecific antibodies have emerged as molecules with a multitude of talents

Bi- and multispecific antibody derivatives (bsAbs) can be considered as the next generation of targeted biologics for cancer therapy. The general concept of bsAbs is a physical connection of recombinant antibody-derived entities with at least two binding specificities. This generates bsAbs that bind at least two antigens or epitopes, thus altering their binding functionalities and specificities in comparison to "normal" antibodies. Most bsAbs are produced as recombinant proteins, either as large IgG-like proteins that contain Fc regions, or as smaller entities with multiple antigen-binding regions but without Fc. Application of bsAbs in experimental cancer therapy currently includes molecules that bind different cell surface proteins to achieve more complete blockage of proliferative or angiogenesis-associated pathways. This approach of blocking more than one pathway component, or to simultaneously hit complementing pathways, also may limit potential escape mechanisms of cancer cells. BsAbs also are applied in the clinic as vehicles to deliver immune effector cells and/or cytokines to tumors.