As outlined in the first part of this article scanning the rapidly evolving technology landscape of bispecific and multispecific antibodies, interest in them has been renewed big time because various manufacturing, stability and safety issues have been addressed. The field now encompasses a multitude of approaches for creating antibodies against a variety of targets and the number of companies entering this space is surging. (See BioWorld Insight, Feb. 19, 2013.)

Although some companies have achieved success with a particular antibody construct in one environment, that doesn't necessarily mean it will operate as well in another. For example, if a construct works well against liquid tumors the same effect might not be seen in solid tumors, Trevor Hallam, chief scientific officer at Sutro Biopharma Inc., told BioWorld Insight.

This one-size-doesn't-fit-all situation means a flexible platform is needed to overcome these circumstances.

The path that Sutro is following is using first-in-class cell biology with protein design to develop a new generation of antibody drug conjugate therapeutics and bifunctional antibody-based therapeutics for targeted cancer therapies.

Sutro's biochemical synthesis technology allows the rapid and systematic exploration of many protein drug variants to identify drug candidates. Once these product candidates are identified, production can be rapidly and predictably scaled up to commercial levels.

Its cell-free protein synthesis system can be scaled up quickly and the company has already made hundreds of grams in hours at scales to 100 liters, Hallam said.

Sutro recently inked a potential $500 million deal with Celgene Corp. that includes two undisclosed targets against which antibody conjugates and bispecific antibodies will be deployed, plus the manufacturing of a Celgene-owned pre-clinical antibody asset.

"The speed of our discovery platform intrigued Celgene," noted Hallam. "When they learned about what we're working on the deal extended from conjugates to bispecifics and included manufacturing. In terms of development we estimate that our technology reduces the clinical development timeline by about 12 months."

Bispecific Antibody Deals

In addition to the expanding number of players in the bispecifics field, the versatile technology available today continues to generate a significant number of significant partnership deals.

Leading the charge in terms of the number of partnerships signed is Adimab LLC, of Lebanon, N.H.

"Over the past three years we have probably signed more partnership deals than any other antibody discovery company," Tillman Gerngross, Adimab's CEO and co-founder, told BioWorld Insight.

Gerngross credits this to its focused business plan, which concentrates on servicing the industry broadly and staying away from selecting particular antibodies for its own internal development.

The company differentiates itself by employing a technology platform, which offers the first fully integrated yeast-based human antibody discovery and optimization program. The system, Gerngross said, provides unprecedented speed from antigen to purified, full-length human IgGs.

In addition to conventional discovery and optimization programs, a lot of interest has been generated in their bispecific platform.

At the beginning of the year, for example, Adimab expanded its existing research collaborations with Whitehouse Station, N.J.-based Merck & Co. Inc. and Indianapolis-based Eli Lilly and Co. The Merck expansion grants the big pharma further access to Adimab's technology to discover and optimize fully human antibody candidates, including potentially bispecific antibody candidates, across all disease areas. Adimab scientists will discover therapeutic antibody candidates to multiple targets nominated by Merck over a three-year period. The expansion of the Lilly agreement will include the discovery and optimization of multiple bispecific antibodies targeting molecular targets identified by Lilly. (See BioWorld Today, Jan. 9, 2013.)

"The antibody discovery arena has become very competitive and nothing is more validating than existing partners coming back for broader access to our platform," noted Gerngross.

Toward Pentaspecific Antibodies

The field is advancing rapidly and we are already moving beyond bispecifics, Peter A. Kiener, president and CEO of Gaithersburg, Md.-based Zyngenia Inc., told BioWorld Insight. "Although bispecific antibodies have tremendous potential, what we are realizing is that going from bi- to potentially pentaspecific antibodies, and being able to tune specificity and valencies, allows you to influence the biology much more effectively."

His company is developing zybodies as their approach to multi-specificity and creating therapeutics that are designed to incorporate the traditional attributes of monoclonal antibodies such as stability, ease of production, half-life, and effector function, into a single antibody-like protein that is able to interact with multiple targets. This multiple target strategy has created many opportunities for therapeutics with new mechanisms of action that are simply cannot be attained using single specificity antibodies.

The company is focusing on a bi-specific antibody targeting inflammation as their first compound that will enter the clinic early in 2014. Kiener said they also have an oncology program that will bring a possible trispecific antibody compound to the clinic by mid-2014.

Like other companies in this space, their versatile platform has also attracted the attention of potential partners and discussions are ongoing in this area, Keiner added.

Biotecnol Inc., of North Brunswick, N.J., is advancing its tribody constructs, which use the natural in vivo heterodimerization of the heavy chain (Fd fragment) and light chain of an Fab fragment to form a scaffold on which additional proteins can be incorporated. As a result Tribodies can incorporate up to three different binding sites and can combine different functions, such as the ability to engage and redirect potent immune-effector cells like T-cells or NK-cells while retaining the ability to target more than one epitope in a tumor target, or more than one target in the same tumor, all in one single molecule.

As an example, the company has generated Tribodies that target both the EGFR and the HER2 tumor antigens and tested that in ex vivo tumors. (See BioWorld Today, June 21, 2012.)

In January they entered into a co-development and exclusive option agreement with Tokyo-based biotech-venture company, Chiome Bioscience Inc. Under the agreement, Tribody molecules will be generated against undisclosed targets, by combining Chiome's own ADLib system, that rapidly generates antibodies by leveraging gene conversion of chicken DT40 cells, and Biotecnol's technology for evaluation and development of multispecific T-cell engager antibodies for cancer treatment.