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An autoimmune option
June 2020
by Mel J. Yeates  |  Email the author
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LEIDEN, the Netherlands—In April, Immutep Ltd. and Batavia Biosciences announced a successful high-yielding cell line for IMP761, an IgG4-based antibody for LAG-3 immunotherapy, which the companies call “an important milestone in the preclinical development of the compound.”
 
This achievement has greenlit the development of a GMP-compliant manufacturing process for IMP761, with the aim of rapidly initiating clinical testing.
 
“IMP761 is the first agonist antibody that targets the immune checkpoint LAG-3 for the treatment of autoimmune diseases such as inflammatory bowel diseases, rheumatoid arthritis and multiple sclerosis,” said Marc Voigt, CEO of Immutep. “We are really pleased with the results generated by Batavia and are excited to be moving closer to clinical testing of this promising product candidate.”
 
Lymphocyte activation gene-3 (LAG-3) is a protein involved in the regulation of the immune system. It was discovered in 1990 by Dr. Frederic Triebel, chief scientific officer and chief medical officer of Immutep. LAG-3 controls the signaling between specific immune cells, T cells and antigen-presenting cells, which are responsible for the adaptive immune response.
 
“T cells are activated through the T cell receptor (TCR) being engaged by a foreign (i.e., coded by a viral RNA or by an oncogene at the tumor site) antigenic peptide, and in some cases by a self-peptide (auto-immune diseases). As an agonist mAb, IMP761 will strengthen the naturally occurring negative signaling of LAG-3 on the antigen-specific TCR activation pathway. Thus, activated T cells expressing LAG-3 at their surface will be downmodulated or ‘silenced’ as long as IMP761 is present above a certain concentration,” Triebel explains. “This concentration is low (10 ng/ml to 100 ng/ml), as it is a potent agonist and only a few percent of LAG-3 molecules on the cell surface need to be engaged by IMP761 to silence the T cell, [as] compared to the high concentrations needed (10 µg/ml to 100 µg/ml) for an antagonist antibody to block 100 percent of its target for many days.”
 
“The second characteristic of IMP761 is that it targets ... specifically the very few memory T cells which are attracted to a given inflammatory site, the source of an immuno-dominant antigenic peptide. This inflammatory site could be a tumor or an autoimmune disease site where these few site-specific peptides chronically stimulate the TCR of these memory T cells, which become ‘exhausted’ and express LAG-3,” Triebel adds. “LAG-3 is therefore an exhaustion marker for memory T cells, and is used here to target these few autoimmune T cells first and then silence them.”
 
According to Triebel, “IMP761 is the only LAG-3 agonist mAb which has been published. It took us more than 20 years to end up finding an agonist LAG-3 mAb, screening hundreds of hybridomas in a functional assay. An mAb to LAG-3 has to touch the right button (i.e., the right conformational B-cell epitope) on the N-terminal domain of LAG-3 (i.e., the one in direct contact with its ligands, MHC class II molecules) to be able to mimic the ligand and strengthen the induced negative signaling mediated by LAG-3. So, quite difficult to find.”
 
“Of course, as the function of LAG-3 is known and numerous blocking LAG-3 mAbs are currently being tested in pivotal trials in immuno-oncology validating LAG-3 as an important target in patients, the potential use of an agonist LAG-3 mAb would be of course in autoimmune diseases (AID),” he states. “For more than 95 percent of AID, the root cause has been defined primarily by a break of tolerance of a few T cells that recognize a given self-antigen (e.g., a skin protein, in the case of psoriasis) too strongly … leading to the killing of the target tissue cells harboring this antigen either by the production of cytotoxic immunoglobulins or the generation of cytotoxic CD8 T cells.”
 
The pharmaceutical-grade, stable CHO cell clones which were developed have provided significantly higher product yields of Immutep’s IMP761 product candidate than the companies had initially anticipated. These results will permit a smooth transition to the development stages. In 2019, Batavia licensed Horizon Discovery’s GS-knockout CHO expression system, CHOSOURCE. The full services package using this system—including cell line generation, process development and manufacturing—is marketed by Batavia as STEP-mAb.
 
“The CHO-K1 cell line used by Batavia has a long history of being used for production of monoclonal antibodies for clinical evaluation and therapeutic use. Batavia’s STEP-mAb platform employs a CHO-K1 cell line from Horizon Discovery where the gene for glutamine synthase … is knocked off using state-of-the-art genome editing. By using glutamine-deficient media and by linking expression of recombinant protein—IMP761, in this case—to glutamine synthase, we are able to isolate only those cells that produce the antibody,” said Dr. Abhinav Luthra, associate director of Batavia Biosciences, and project manager for the Immutep project. “Additional metabolic pressure is applied during cell selection by means of a glutamine synthetase inhibitor. All these factors—including a robust cell line, effective expression vectors and workflows to select cell lines with desired characteristics—enable us to produce cell lines with the highest possible expression level.”
 
“Our current efforts have resulted in a pharmaceutical-grade cell pool that produces a high-level of functionally active IMP761,” Luthra adds. “We have started the process of isolating clonal populations from this pool that will give us consistent performance during a large-scale manufacturing. This process, also involving fully characterizing the resultant cell clones, is expected to take eight to 10 months.”
 
As well as readying IMP761 for GMP manufacturing, the companies plan to prepare a preclinical package for IND submission to the FDA.
 
Code: E062013

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