While the accelerated approval in December of Amgen Inc.'s Blincyto (blinatumomab) heralded the arrival of bispecific antibodies, it's just the start. Other companies are quickly queuing up and bringing new technologies into the mix such as Cytomx Therapeutics Inc., which is working on Probodies, and Xencor Inc., with its Xmab technology for engineering changes in the Fc domain. Early stage firm Zymeworks LLC, meanwhile, is advancing a B-lymphocyte antigen CD19 modulator in a deal with Merck & Co. Inc. (See BioWorld Today, Feb. 9, 2015.)

But the industry is rife with other approaches. Abbvie Inc., of North Chicago, has three bispecifics in development, including ABT-122, a dual anti-tumor necrosis factor (TNF)/IL-17 ligand inhibitor that has one phase II under way and a second planned, according to Cortellis Clinical Trials Intelligence. A second TNF ligand inhibitor and a dual IL-12/IL-18 ligand inhibitor remain in discovery.

Ablynx NV, of Ghent, Belgium, is advancing two bispecific candidates from its nanobody platform: the von Willebrand factor ligand inhibitor caplacizumab (subcutaneous) to treat thrombocytopenic purpura, and ozoralizumab, a TNF alpha ligand inhibitor, targeting inflammatory disease. Both have advanced to phase II. (See BioWorld Today, June 18, 2014.)

Medimmune, of Gaithersburg, Md., has an anti-Psl/PcrV multispecific monoclonal antibody in discovery to treat Pseudomonas aeruginosa infection. The global biologics research and development arm of Astrazeneca plc also has MEDI-3902, a PcrV protein type III modulator, in phase I development in the same indication.

Paris-based Sanofi SA has moved SAR156597, a bispecific antibody targeting interleukin-4 and interleukin-13, into phase II development in idiopathic pulmonary fibrosis.

And Roche AG unit Genentech has a bispecific molecule in discovery to treat wet age-related macular degeneration and duligotuzumab, an EGF antagonist and Erbb3 tyrosine kinase receptor inhibitor, in phase I development to treat solid tumors.

Enthusiasm about the scientific underpinnings and potential of bispecifics – or multivalent antibodies, as some prefer to call them – has fueled dealmaking in the space. And nearly everyone expects to see more.

"There's a gorgeous proliferation of technologies now, fueled by the general health of our industry," said Laura Vitez, principal business analyst for Thomson Reuters Recap. The flow of capital "allows increased investment in innovation and increased alternatives to move forward the results of that innovation," whether through M&A deals, initial public offerings, "interesting and mutually fulfilling" licensing deals or continued venture funding, she added.

'PHARMA WILL CONTINUE TO MAKE DEALS IN THIS SPACE'

An exhaustive look at the bispecific space is nearly impossible, but a sampling of deals suggests the vigor of the technology.

In June 2013, Immunocore Ltd., of Oxford, UK, inked a multitarget deal with Genentech to generate bispecific constructs called Immtacs, or Immune mobilizing mTCR against cancer, designed to exploit the power of T-cells to recognize peptide antigens that are produced by tumors. The deal was valued at a potential $320 million or more per program, plus royalties, with Genentech handing over two targets at the outset. (See BioWorld Today, June 27, 2013.)

Days later, Immunocore inked a potential $525 million discovery agreement with Glaxosmithkline plc, of London, to discover bispecific Immtacs against multiple targets that could not be addressed with antibody-based technologies. (See BioWorld Today, July 9, 2013.)

In December 2013, Oncomed Pharmaceuticals Inc., of Redwood City, Calif., signed a potential $3 billion deal with Celgene that included $177.25 million up front, $22.25 million as an equity investment and options on up to six oncology candidates. The lead candidate in that deal was demcizumab, which targets Delta-like ligand 4 and was undergoing phase Ib testing in non-small-cell lung cancer and pancreatic cancer. But payments for an undisclosed asset in the lineup, an anti-DLL4/VEGF bispecific antibody, could amount to as much $505 million. (See BioWorld Today, Dec. 4, 2013.)

Hedging its bets, Celgene inked two additional bispecific deals with Sutro Biopharma Inc., of South San Francisco. A potential $500 million pact in 2012 led to a broader collaboration last year – and one with a buyout option. The specifics of those antibodies remain under wraps, but both are targeting cancer. (See BioWorld Today, Dec. 19, 2012, and Oct. 24, 2014.)

Prowess in bispecific antibody development drove Johnson & Johnson's $218 million acquisition of Covagen AG, of Schlieren, Switzerland. The small biotech, which is developing engineered binding proteins called Fynomers derived from the Src homology 3 domain of Fyn tyrosine kinase, already had a lead asset in a phase II program with three others in discovery, according to Cortellis CI. (See BioWorld Today, Aug. 27, 2014.)

Late last year, Janssen Biotech Inc. inked a potential $675 million deal for MGD-011, from Macrogenics Inc., which targets CD19 and CD3 as a potential treatment for B-cell malignancies. (See BioWorld Today, Dec. 23, 2014.)

Sean McCarthy, CEO of Cytomx, also pointed to Roche's potential $488.75 million acquisition of Dutalys GmbH, of Vienna, which specializes in the discovery and development of bispecific antibodies based on its Dutamab technology. "Roche obviously has incredibly deep experience in biologics, including experience in bispecific of their own, but they still saw value in going after the market and acquiring a novel platform with its own twist on how to create and optimize bispecific formats," he said. "That's one of the very strong signals that pharma will continue to make deals in this space."

As Recap's Vitez observed, even small companies with bispecific assets are attracting funding to advance their internal pipelines. In February 2014, Geneva-based Novimmune SA closed a series B financing round for CHF60 million (US$66 million) to advance multiple candidates, including two assets from its kappa/lambda body bispecific drug platform, NI-1701 and NI-1801, that may selectively inhibit CD47 on cancer cells.

Other names in the space include Adimab LLC – which inked yet another bispecific deal, with Sanofi, just last week – F-star Biotechnology Ltd., Innovent Biologics Inc., Mabvax Therapeutics Inc., Merus BV, Sorrento Therapeutics Inc., Swedish Orphan Biovitrum AB, Tesaro Inc. and Triphase Accelerator Corp.

In short, the roster of bispecific antibody developers reads like a Who's Who of the biopharma industry. All told, Cortellis CI identified 83 bispecific antibodies in development – three-fourths still in discovery and most targeting oncology indications – with almost as many companies involved as sponsors or partners and using a variety of target-based actions.

'WE'RE GOING TO SEE A FLOOD OF BISPECIFIC MOLECULES'

Moving forward, it's clear that "the drug development world wants bispecific antibodies that can be readily manufactured and, very importantly, have the same manufacturing protocols as their monovalent antibodies because that affects their cost of goods," Zymeworks CEO Ali Tehrani observed. "They don't want to change processes. They don't want to change their purification protocols. They don't want to change their cell line development protocols. They don't want new vectors."

A number of companies now have the technology to address those challenges while still providing the flexibility that pharma also seeks, he added.

"This is the future," Tehrani said. "Whether it's our bispecific or someone else's bispecific, the one sentiment we hear is that the industry needs to combine biologies – not in a cocktail format but in a single, targeted drug format. It is possible now, and I believe drug design in the next five to 10 years is going to be dominated by bispecifics."

The big question for the field now is which technologies, and companies, will survive the inevitable winnowing as competing assets seek to prove their mettle in the clinic, which could be a daunting task.

In light of Blincyto's approval, "it's a little easier to see – maybe a lot easier to see – the path to market for bispecifics" compared to related technologies such as CAR-T cells, McCarthy observed. "But the technical challenges we've been grappling with remain. What is the right relative affinity of the two binding arms of a bispecific? What is the right format, in terms of the presentation of those two antigen-binding arms? How do those formats relate to manufacturability and overall CMC considerations? And what are the right pairings or targets to really drive efficacy?"

The field has learned a great deal, and the tipping point was Blincyto's approval, he added, but that won't remove all of the twists and turns in the road ahead.

"It's noteworthy that most if not all of the late-stage clinical work so far is in hematologic malignancy," McCarthy said. "How do we extend the technology to solid tumors? That's where the field is wrestling with the challenge of target selection and target distribution. The doses of a T-cell engaging bispecific are so much lower than that of a conventional therapeutic antibody and the potency of these molecules is so much higher – given the cell-based efficacy and the amplification that one obtains by recruiting professional killers to the tumor – that to have a therapeutic index, targets will have to be carefully addressed."

But the field is moving rapidly to overcome those challenges, maintained Bassil Dahiyat, co-founder, president and CEO of Monrovia, Calif.-based Xencor.

"We're going to see a flood of bispecific molecules enter and advance through the clinic in the next two to three years," he predicted. "We're really at the early days of the platforms that are going to change the landscape."

Editor's note: Part one of this in-depth look at bispecific antibodies discussed the way the number of technologies and pipelines have exploded in recent years. Part two takes a look at some of the other approaches in development and explains why the industry can expect to see more.

BioWorld Insight is the weekly news service that provides behind-the-scenes analysis and commentary on the biopharmaceutical marketplace. Subscribe by calling (770) 810-3144 or (800) 477-6307 if calling from the U.S. or Canada or email bioworld at salessupport@thomsonreuters.com.