Current progress in innovative engineered antibodies

Abstract

As of May 1, 2017, 74 antibody-based molecules have been approved by a regulatory authority in a major market. Additionally, there are 70 and 575 antibody-based molecules in phase III and phase I/II clinical trials, respectively. These total 719 antibody-based clinical stage molecules include 493 naked IgGs, 87 antibody-drug conjugates, 61 bispecific antibodies, 37 total Fc fusion proteins, 17 radioimmunoglobulins, 13 antibody fragments, and 11 immunocytokines. New uses for these antibodies are being discovered each year. For oncology, many of the exciting new approaches involve antibody modulation of T-cells. There are over 80 antibodies in clinical trials targeting T cell checkpoints, 26 T-cell-redirected bispecific antibodies, and 145 chimeric antigen receptor (CAR) cell-based candidates (all currently in phase I or II clinical trials), totaling more than 250 T cell interacting clinical stage antibody-based candidates. Finally, significant progress has been made recently on routes of delivery, including delivery of proteins across the blood-brain barrier, oral delivery to the gut, delivery to the cellular cytosol, and gene- and viral-based delivery of antibodies. Thus, there are currently at least 864 antibody-based clinical stage molecules or cells, with incredible diversity in how they are constructed and what activities they impart. These are followed by a next wave of novel molecules, approaches, and new methods and routes of delivery, demonstrating that the field of antibody-based biologics is very innovative and diverse in its approaches to fulfill their promise to treat unmet medical needs.

Keywords: antibody clinical candidates; chimeric antigen receptors; engineered antibodies.

Figure 1

Cartoons of molecules and constructs discussed. (A) IgG monoclonal antibody; (B) FAb fragment; (C) Single chain fragment, variable (scFv); (D) Heterodimeric IgG-based bivalent, bispecific antibody; (E) scFv-based bispecific antibody such as a BiTE (“bispecific T-cell engager”); (F) IgG-scFv-based tetravalent, bispecific antibody; (G) Tetravalent scFv-based antibody called TandAb; (H) IgG-based Immunocytokine (cytokine is denoted by green oval); (I) Tandem scFv-immunocytokine (cytokine is denoted by green oval); (J) Fc-peptide fusion (peptides denoted by squiggled lines); (K) Fc-protein fusion (protein denoted by gray oval); (L) Antibody drug conjugate with three parts (antibody, linker, cytotoxic drug); (M) Chimeric antigen receptor (CAR)-T based antibody (scFvs on surface of recombinant T cell; examples of intracellular domains noted in box)

Figure 2

Small molecule drugs (blue lines), biologics including vaccines (green lines), and monoclonal antibodies/Fc fusion proteins (red lines) approved by the United States Food and Drug Administration from 1997 to May 1, 2017. This information was sourced and extracted from the US FDA website (https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm537040.htm)

Figure 3

Five basic types of bispecific antibodies. (A) Bivalent, bispecific IgG-like antibodies with heteromeric heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc); (B) Tetravalent multispecific antibodies comprised of IgGs with other binding domains fused to either the N- or C-termini of either the heavy or light chains (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG with non-antibody binding scaffold “centyrin” fused to C-terminal end of heavy chains); (C) IgGs to which additional antigen combining sites have been added within the structure (e.g., two-in-one antibodies, MAT “Modular Antibody Technology” platform from F-Star); (D) Engineered antibody fragments linked by short peptide linkers which can be made into bivalent, trivalent, or tetravalent formats addressing two to three targets (e.g., bispecific T-cell engager (BiTE), Nanobody platform, dual- affinity re-targeting (DART) antibodies, “tandem antibody” structures (TandAbs)); (E) Chemically coupled IgGs