New Drug Platform
There is a long history of bi-specific antibodies attempting to engage T cells, but none of these early attempts worked well. Micromet has developed novel proteins using its BiTE® technology. This involves using recombinant DNA, whereby the two binding domains of a T-cell binding antibody are connected by a linker sequence to become one polypeptide—a single-chain antibody. This process is repeated with a second antibody binding a cancer cell. The two different single-chain antibodies are finally connected with a third linker.
“The advantage of the novel protein is that it is small (only 55 Kd) compared to a regular antibody (150 Kd),” explained Patrick Baeuerle, Ph.D., senior vp, R&D and CSO. Another advantage is that it is produced as a single polypeptide encoded only by one gene. The linkers are of low immunogenicity because they lack hydrophobic amino acids.
“There have been no immune responses to BiTE antibodies in clinical trials to date,” added Dr. Baeuerle. In addition, the linker sequence is flexible, allowing the antibody to grab two epitopes on two opposing cell surfaces.
A key factor is the way these antibodies bind to T cells—only if the BiTE is presented to T cells on the surface of a target cell will it activate the T-cell receptor CD3. If it binds to the T cell with just one arm, the T cells are not activated. This safeguard mechanism is a core feature of the technology and is referred to as conditional T-cell activation.
The company currently has two BiTE antibodies in clinical studies. MT103 (blinatumomab) binds CD19, present on lymphoma cells and MT110 binds to an epithelial cell adhesion molecule (EpCAM) present on most solid tumors.
The company recently showed data (in vitro and mouse assays) confirming that MT110 eradicates colorectal cancer stem cells expressing EpCAM, Dr. Baeuerle noted. Additional data demonstrated that a BiTE antibody developed from the binding domains of Erbitux can engage T cells and overcome the limitation of this mAb. Human colorectal cancer cells mutated in KRAS and BRAF genes were efficiently killed in a mouse model by the Erbitux-based BiTE antibody, while Erbitux was ineffective, he added.