BiTE antibodies

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BiTE antibodies (from English Bi-specific T-cell engagers ) are artificial bispecific monoclonal antibodies . They consist of two scFv fragments that are linked by a peptide bridge . One of the two scFv fragments exhibits selectivity for an antigen on a target cell. The other scFv fragment is able to bind specifically to surface proteins of T cells . In this way, with the help of BiTE antibodies, a T-cell-mediated immune response against certain target cells, such as tumor cells , can be controlled in a targeted manner. BiTE antibodies, which were largely developed by the biotechnology company Micromet ( bought by Amgen in 2012 ), are therefore being explored as a new option in tumor therapy. Blinatumomab is the first BiTE antibody used therapeutically.

structure

Schematic representation of the structure of a BiTE antibody

BiTE antibodies consist of two scFv fragments and have a molecular mass of about 55  kDa . Each of the scFv fragments consists of a variable domain of the light (V L ) and a variable domain of the heavy chain (V H ) of a conventional monoclonal antibody. These four domains are linked to one another via peptide bridges to form a single amino acid chain. In terms of development and production, this structural property is an advantage over conventional IgG antibodies consisting of a total of four chains . BiTE antibodies can be compiled with the help of molecular biological methods, coded by a single gene and obtained with conventional biotechnological methods using eukaryotic cell lines.

function

BiTE antibodies bind simultaneously to a T cell and a target cell (here: tumor cell)

The two scFv fragments, from which a BiTE antibody is built, are able to bind bispecifically to two different target proteins. By definition, an scFv fragment always binds to a surface protein of the T cells, usually the CD3 receptor . The second scFv fragment is directed against a surface protein that is expressed as selectively as possible on the target cell. By binding to the corresponding target proteins, BiTE antibodies link a target cell with a T cell. The T cell is activated in this way and begins to produce and release cytotoxic proteins, such as the pore-forming protein perforin and granzyme , which trigger programmed cell death ( apoptosis ). As a result, the target cell is destroyed.

This mechanism is based on the natural function of the cytotoxic T cells. The T-cell-mediated recognition and destruction of a target cell using BiTE antibodies is, however, independent of the involvement of the major histocompatibility complex (MHC).

use

BiTE antibodies are being discussed in particular as a possible new option in tumor therapy. The BiTE antibody blinatumomab , which is directed against CD3 and CD19 , is currently being tested in clinical studies . Further BiTE antibodies against CD3 and EpCAM , HER2 / neu , EGFR , CD66e , CD33 , EphA2 and MCSP are in development. Blinatumomab was approved in the EU in November 2015 for the treatment of specific forms of acute lymphoblastic leukemia (ALL) . It was approved in the USA in December 2014.

Individual evidence

  1. ↑ a b c Baeuerle PA, Reinhardt C: Bispecific T-cell engaging antibodies for cancer therapy . In: Cancer Res . 69, No. 12, June 2009, pp. 4941-4. doi : 10.1158 / 0008-5472.CAN-09-0547 . PMID 19509221 .
  2. ↑ European Commission Approves Amgen's BLINCYTO® (blinatumomab) for the Treatment of Adults with Philadelphia Chromosome-Negative Relapsed or Refractory B-precursor Acute Lymphoblastic Leukemia , PM AMGEN of November 24, 2015, accessed on November 24, 2015.
  3. ↑ Blinatumomab , FDA notification dated December 3, 2014, accessed November 24, 2015.

literature