DUBLIN – Shares in Medigene AG rose nearly 17 percent Thursday on news of an alliance with Bluebird Bio Inc. to develop T-cell receptor-based immunotherapies, in which it is getting $15 million up front plus more than $1 billion in potential milestone payments covering preclinical and clinical development, regulatory approval and product sales.

The full scope of the deal covers four TCR-based therapies across several undisclosed cancer indications. Medigene will also receive research funding over the three-to-four year term of its active R&D collaboration with Bluebird Bio and tiered royalties on eventual sales, ranging from single to double digits.

Shares of Medigene (FRANKFURT:MDG1) gained €1.17 (US$1.31), to close at €8.07.

Martinsried-based Medigene's TCR therapy approach is based on the adoptive transfer of autologous T cells that have been engineered ex vivo to express a TCR directed against a specific tumor antigen. "We can address both liquid tumors and solid tumors with our technology," Chief Operating Officer Dave Lemus told BioWorld Today. It has created a library containing TCRs directed against a diverse array of tumor antigens. "There's dozens of them so far in our collection," he said.

That's a major point of differentiation against developers of chimeric antigen receptor (CAR) T cells. The latter are currently limited to a narrower spectrum of targets expressed on the cell surface. Medigene's approach encompasses the much larger universe of intracellular targets. "It's the next step beyond CARs," Medigene's CEO and chief scientific officer, Dolores Schendel, told BioWorld Today. Antigen presentation is by necessity major-histocompatibility-complex (MHC)-restricted, however.

Identifying high-affinity, tumor-directed cytotoxic T-lymphocytes is not a trivial undertaking. In normal circumstances, they undergo thymic deletion as part of the body's immune tolerance mechanism.

Medigene's TCR technology is an extension of its existing dendritic cell vaccine platform. It transfects dendritic cells obtained from healthy donors with RNA encoding an allogeneic MHC molecule and a tumor-associated antigen to generate what Schendel and colleagues have described as "allo-restricted peptide-specific T cells."

Any MHC molecule can be combined with any tumor-associated antigen in a dendritic cell, which is then used to prime autologous T cells. The resulting TCRs can be isolated using a variety of screening techniques and then introduced to patients' T cells ex vivo, before subsequent administration of the engineered T cells.

The approach was described in the Sept. 3, 2009, issue of Blood, in a paper, titled "Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior antitumor activity and higher TCR functional avidity."

The company has a battery of in silico and in vitro tests designed to pick up on potential cross-reactivity between a target epitope found on a tumor-associated antigen and any similar off-target epitopes residing in proteins expressed by healthy tissues. "You try to find the optimal affinity. It's very dependent on the selection of the target antigen," Schendel said.

Medigene's in-house TCR-based immunotherapy programs are still at the preclinical stage. The company is also collaborating with the Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC), Berlin, and the Charité University Hospital Berlin (Charité – Universitätsmedizin Berlin) on the first trial in Germany of a TCR-based therapy. The investigator-initiated study involves the administration to melanoma patients of autologous T cells engineered to recognize melanoma-associated antigen 1 (MageA1). Medigene did not generate the MageA1-specific TCR, but it is providing advice on the analytics and GMP aspects of the project, as well as handling its regulatory dimensions.

"Everything we learn here will be highly applicable to our own programs that will follow in the second half of 2017 and in 2018," Lemus said. Moreover, the company retains an option to negotiate a commercial license to the project.

The timing of the first trials under the alliance with Bluebird Bio, of Cambridge, Mass., is unclear at this point. "That's very much in the hands of Bluebird Bio," Lemus said. The two companies will collaborate on preclinical development – they will employ Bluebird Bio's lentiviral vector technology for engineering TCRs into patients' T cells. Bluebird Bio will have sole responsibility for clinical development and commercialization.

Shares of Bluebird (NASDAQ:BLUE) closed Thursday at $66.40, down $2.70.

The deal is a significant boost to Medigene's credentials as a credible player in immuno-oncology. It missed the boat the first time around by acquiring and then disposing of Avidex Ltd., the company whose IP gave rise to two heavy hitters in immuno-oncology, Oxford, U.K.-based Immunocore Ltd. and Oxford-based Adaptimmune Therapeutics plc. It belatedly returned to the area in early 2014 by acquiring Trianta Immunotherapies GmbH, a spinout from the Munich Helmholtz Center (Helmholtz Zentrum München) based on Schendel's research. (See BioWorld Today, Jan. 28, 2014.)

Adaptimmune and Immunocore are developing, respectively, cell-based and protein-based therapies that rely on engineered TCRs. Immunocore's Immtac bispecific molecules direct a T-cell response against a cancer by combining a TCR that recognizes a cancer antigen with a humanized anti-CD3 single-chain variable antibody fragment (scFv) that engages T cells. Adaptimmune has two programs in clinical trials, both based on its Spear (Specific Peptide Enhanced Affinity Receptor) technology, which employs affinity engineering to optimize antigen recognition.

NY-ESO TCR, which is partnered with London-based Glaxosmithkline plc, is undergoing phase I/II studies in synovial sarcoma, multiple myeloma, ovarian cancer, melanoma and non-small-cell lung cancer (NSCLC). MAGE A-10 TCR is undergoing a phase I/II trial in NSCLC at present and is slated to enter trials in ovarian cancer, bladder cancer and melanoma. Immunocore has several trials underway testing an Immtac molecule that recognizes melanoma-associated antigen gp100 – monotherapy and combination studies are ongoing in melanoma patients. Some of the main CAR T-cell therapy developers also have TCR programs underway, including Juno Therapeutics Inc., and Kite Pharma Inc.

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