April 1, 2010 (Vol. 30, No. 7)

Firm Strives to Exploit Antibody Structures Made by the Body

Conventional antibody discovery methods poorly detect antigens cloaked in carbohydrates or lipids. Scientists at Calmune in San Diego are creating new technology platforms that overcome such limitations to uncover potent antibodies against infectious viruses, bacteria, and fungi. “Calmune offers new ways to generate antibodies against targets that have not adequately been addressed by conventional technologies,” says president and CEO Anthony Williamson, Ph.D.

Some of the technology under development at Calmune was licensed from the Scripps Research Institute, where Dr. Williamson was an associate professor. He left Scripps and co-founded Calmune in 2006 along with colleagues Dennis Burton, Ph.D., and Pietro Paolo Sanna, Ph.D. The three researchers collaborated at Scripps on investigations into human antibody responses to infectious pathogens using phage-display libraries.

“We became aware that there were a number of antibodies elicited during the course of a natural infection, particularly viral infections, that were extremely potent biologically,” says Dr. Williamson. The men founded Calmune to exploit antibody structures that have arisen naturally and are a response to immunologically challenging antigens.

A prime example is the company’s DXAb antibody discovery platform. Short for “domain exchange antibodies,” the process was first identified in a neutralizing antibody that binds to human immunodeficiency virus (HIV). Generally, antibodies bind poorly to carbohydrate antigens.

This unusual antibody, however, recognizes carbohydrates on the surface of HIV and neutralizes the virus. Mutations in the antibody’s framework cause a domain exchange in the heavy chain variable regions, resulting in an unusual linear structure instead of the usual Y-shape of conventional antibodies. The altered structure contains an array of fixed and closely spaced combining sites that are ideal for recognition of repetitive carbohydrate residues on the surface of HIV.

This rare linear structural motif evolved naturally in the body’s response to HIV infections. Calmune scientists are manipulating the structure to create high-affinity, fully human monoclonal antibodies that recognize carbohydrate groups on a variety of clinically important microorganisms.

The approach could lead to new treatments for infectious diseases, since many pathogens use carbohydrates to shield themselves from the immune system. “This is a way to overcome that protection by designing extremely specific anticarbohydrate antibodies that could be directed against sugars found on the surfaces of pathogens,” notes Dr. Williamson.

Another new platform, called Membrane Proximal Antibodies, is closely related to DXAb and also was discovered in HIV. Membrane Proximal Antibodies show a preference for binding to antigens associated with lipids on cell membranes. As with  carbohydrate recognition, most antibodies do not bind readily to lipid-associated antigens.

Company scientists are working to preserve the general features of the novel antibody structures that predispose them to bind to lipids and carbohydrates, but they are changing the binding pockets to make antibodies specific for other pathogens. “We’re taking something designed by the ingenuity of human immune system and trying to harness it more generally to make antibodies against other infectious agents,” Dr. Williamson says.

Penetration of topically delivered AC8 Fab antibody into the cornea

First Commercial Collaboration

Calmune’s most advanced platform, SEBVI™, uses Epstein Barr virus to immortalize and clone human B cells that secrete IgG antibodies. The SEBVI technology “allows us to mine existing antibody responses in memory B cells from individuals who are naturally infected with a pathogen of interest,” explains Dr. Williamson. Then the antibody responses are broken down to the molecular level to find antibodies that most potently neutralize an infectious agent.

In November 2009, Calmune teamed up with Crucell to use SEBVI to prepare a panel of potent, high-affinity human monoclonal antibodies against infectious disease targets associated with respiratory illnesses. “The alliance is a good fit,” says Dr. Williamson, because “Calmune mainly is a discovery and research company, and Crucell has world-class expertise in antibody development and manufacturing.”

Crucell is Calmune’s first commercial collaboration. For other potential collaborators, Calmune’s platforms can offer answers to difficult antigenic questions and find new ways to generate antibodies against targets. 

Calmune’s pipeline also includes AC-8, a potential therapy for herpes simplex virus (HSV) eye infections, which causes conjunctivitis, keratitis, and iritis. The cumulative damage from HSV infections is the most common cause of corneal blindness in the U.S. AC-8 contains antibody fragments that attack HSV-1 and HSV-2 and prevent cell-to-cell virus spread. Preclinical animal models will determine whether AC-8 reduces the HSV viral load and prevents keratitis. If so, the company will pursue AC-8 as a possible therapy for recurrent HSV eye infections.

Calmune’s initial focus is on finding antibodies to treat respiratory pathogens, such as respiratory syncytial virus and influenza, as well as antibodies to prevent or treat hospital-acquired bacterial infections, such as MRSA. These pathogens continue to find new ways to thwart the immune system and existing drugs. By harnessing the best antibodies made naturally by the immune system, Calmune hopes to augment or replace current treatments for resistant infections.

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