MacroGenics hits winning target

Biotech firm’s DART antibody technology nabs potential $2.1 billion deal with Boehringer Ingelheim

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ROCKVILLE, Md.—The year 2010 ended with a bang as MacroGenics, a private, venture-backed biotechnology company specializing in novel biologics for autoimmune disorders, cancer and infectious diseases, signed a deal with German pharma Boehringer Ingelheim that could be worth more than $2.1 billion.

The deal, one of the year's largest in terms of potential worth, aims to discover, develop and commercialize antibody-based therapeutics spanning multiple therapeutic areas, including immunology, oncology, respiratory, cardiometabolic and infectious diseases.

At the heart of this deal is MacroGenics' Dual-Affinity Re-Targeting (DART) platform, a bispecific antibody technology that enables the generation of highly stable antibody-based therapeutic molecules that can simultaneously target two different antigens. In this deal, the DART platform will be directed against up to 10 combinations of molecular targets.

Combining the DART platform with Boehringer Ingelheim's resources has the potential to "generate breakthrough medicines that will help patients with a range of diseases which cannot be adequately treated at present," said Prof. Wolfgang Rettig, senior vice president of corporate research of Boehringer Ingelheim, in a statement. Boehringer Ingelheim recently published data from a new clinical trial of afatinib, an oncology therapy, showing its efficacy against non-small cell lung cancer.

MacroGenics CEO Scott Koenig says the biotech recently presented public data on DART's success—in the American College of Rheumatology's Arthritis & Rheumatism and Elsevier's Journal of Molecular Biology—which attracted Boehringer Ingelheim to the capabilities and performance of the platform.

"This ultimately led to negotiations," Koenig says. "We think it is a commitment and recognition of the strength of the DART platform, as Boehringer Ingelheim has historically been one of the major leaders in biologics. If you ask people who were pioneers in manufacturing of antibodies, they definitely put Boehringer Ingelheim at the top of the list."

In addition to its high price tag, the deal is unique in another respect, as both companies will share responsibility for discovery and certain preclinical activities. Boehringer Ingelheim will have sole responsibility for all subsequent preclinical, clinical, regulatory, commercial and manufacturing activities for any DART-based product resulting from the collaboration.

MacroGenics stands to receive about $60 million in an upfront cash payment, annual maintenance fees, R&D funding and near-term research-based milestones during the first three years of the collaboration. The biotech is also eligible to receive up to $210 million in development, regulatory and commercial milestone payments for each of the 10 DART programs if they are successful, as well as tiered royalties on net product sales.

MacroGenics has the option to co-promote certain DART products in the United States.
In explaining the DART platform's modalities, Koenig creates a mental picture of a molecular entity with two arms and a tail. The platform is focused on dual-specificity, "antibody-like" therapeutic proteins capable of targeting multiple different epitopes with a single recombinant molecule, and is specifically engineered to accommodate virtually any variable region sequence in a "plug-and-play" fashion with predictable expression, folding and antigen recognition.

A key technological advancement and distinguishing feature of MacroGenics' DART is a proprietary covalent linkage, which results in a molecule having superior stability, optimal heavy and light chain pairing and predictable antigen recognition. The platform is highly flexible and yields an array of product possibilities including, modulation of receptor signaling events, redirected effector cell killing, targeting multiple cytokines or receptor ligands with a single molecule and targeting multiple epitopes on a pathogen for enhanced neutralization and/or clearance.

"In one configuration, one DART arm can recognize the target of one cell, and the other DART arm can recognize a molecule on another cell," Koenig explains. "For example, in this version of the DART, a T cell brought in close proximity to a tumor cell will become activated and destroy the cancer cell. In a second configuration of the platform, two distinct pathways may be targeted to regulate cell growth or activation. For example, a cancer cell or inflammatory cell may require two or more independent growth factors to survive or function. Ordinarily, a drug or monoclonal antibody can target only one pathway or growth factor at a time. By targeting two pathways in a single recombinant DART molecule, it is possible to modulate the growth or activity of these cells in an additive or synergistic manner."

MacroGenics believes that its minimal linker size and content decreases the potential for immunogenicity. The company has been able to produce DART molecules in both bacterial and mammalian expression systems. To date, MacroGenics has produced more than 60 different DART molecules and has completed in vitro and in vivo proof-of-concept studies.

On the heels of this deal's announcement, MacroGenics said that it will also work with Pfizer Inc. to discover, develop and commercialize DART products directed at two undisclosed cancer targets. Calling MacroGenics' DART candidates "a promising new approach to potentially expand treatment options for cancer patients," Pfizer has agreed to give MacroGenics an upfront payment, milestones and royalties, the specific financial terms of which were not released.

Both deals were welcome news for MacroGenics, which announced in October that it and development partner Eli Lilly & Co. were forced to suspend a clinical trial of teplizumab, an experimental diabetes drug, when it failed to meet its primary efficacy endpoint. Had it been successful, the drug was expected to give MacroGenics a $1 billion revenue boost.

MacroGenics' recent low, followed by recent highs, "shows the good and bad side of biotechnology," Koenig says. He notes that Boehringer Ingelheim expects to make a future equity investment in MacroGenics. In addition to these collaborations, MacroGenics has also been working with Korea's Green Cross since July on the exclusive development and commercialization of MGAH22, an anti-HER2 monoclonal antibody. A multinational Phase I study will be conducted in both the United States and Korea.

"We have unique talents in this organization," he asserts. "When I recruited many of the senior people in this organization, I looked for those who had the experiences and skill sets to take molecules through late-stage clinical development, regulatory processes and commercialization, so the learning curve here is not steep at all. A lot of these other companies appreciate that about MacroGenics and see us as a partner that has deeper experiences compared to others in the biological space, and come at this with a broad knowledge base."

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