Unlocking the potential of laboratory-grown recombinant polyclonal antibodies

How does GigaGen’s single-cell discovery and development platform differ from traditional methods of producing polyclonal antibody therapies?

While current polyclonal antibody (pAb) therapies are derived from plasma, GigaGen has developed single cell discovery and development platforms to produce diverse and potent recombinant pAb therapies that are manufactured in the laboratory. This technology captures millions of individual B cell antibody sequences from convalescent or vaccinated donors and replicates the most potent and neutralizing antibodies that target a specific pathogen. The final product contains thousands of antibodies, is typically thousands of times more potent than similar plasma-derived therapies, can be produced from a single cell bank in a single manufacturing step, and can be purified using methods similar to monoclonal antibodies (mAbs).

Current methods for producing monoclonal antibody therapies rely on regular plasma donations. Plasma-derived monoclonal antibody products can be used to prevent and treat infections and are less resistant to escape mutations than monoclonal antibodies because the product is composed of diverse antibodies from many donors. However, the most potent and effective plasma donations are difficult to find and must be constantly replenished.

We have seen monoclonal antibodies used to treat infections, but a single antibody often does not have the ability to neutralize variants that emerge (for example, as seen with monoclonal antibodies targeting severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) that have lost their effectiveness against new variants). It is possible to circumvent pathogen escape by mixing a cocktail of individually manufactured monoclonal antibodies. However, it remains a time-consuming and expensive process to identify the best individual antibodies, which must then be manufactured in separate manufacturing and purification runs.

GigaGen’s single-cell recombinant technology enables the selection and replication of a highly specific and diverse antibody response, which can also be engineered to create therapies more potent than those provided by a natural immune response. These therapies can also be scaled up efficiently in the laboratory, without the need to continually find new donors. With this novel approach, GigaGen’s products exhibit remarkable lot-to-lot consistency and enable the generation of highly potent and highly diverse therapies that can target a broad range of diseases.

In what ways can GigaGen’s laboratory-made recombinant polyclonal antibodies be enriched or modified to improve their therapeutic potency compared to natural antibodies?

GigaGen’s recombinant pAb products are created by copying and replicating the best immune responses from human donors. After isolating the genetic sequences for each antibody from millions of B cells, the antibody sequences are expressed on the surface of yeast (called yeast display). Using fluorescently labeled antigens for any pathogen or target of interest, the antibody sequences that bind to the antigen are illuminated and can be extracted from the mixture to enrich for only the most potent antibodies against the pathogen. For example, to make our hepatitis B virus (HBV) treatment, we used B cells from vaccinated donors and enriched for antibodies targeting multiple variants of the hepatitis B surface antigen (HBsAg). The final product contains over 1,000 antibodies and is over 2,000 times more potent than a plasma-derived hyperimmune HBV. Depending on the needs to combat an infection, recombinant pAbs can be bioengineered, for example to increase the half-life of the treatment or to enhance its ability to induce antibody-mediated immune responses to help clear the infection.

What are the advantages of using recombinant polyclonal antibodies derived from human donors who have shown strong immune responses to specific diseases, as opposed to antibodies from human or animal plasma?

Recombinant pAbs and plasma-derived antibody therapies can be initiated with highly responding donors. However, recombinant pAbs do not rely on continuous plasma sources for their production. Additionally, they are more potent than human or animal plasma-derived therapies because we enrich only the most potent antibodies from the most responsive donors for inclusion in our products. Produced under controlled laboratory conditions, recombinant pAbs offer rapid scalability, unlimited supply, and consistent quality.

How has GigaGen’s platform demonstrated its versatility through its botulinum toxin program?

GigaGen’s platform has completed a broad preclinical pipeline of recombinant pAbs being evaluated for the treatment of chronic hepatitis B, immunodeficiency, transplant rejection and rabies. GigaGen’s botulinum toxin program, currently being developed under contract with the U.S. Department of Defense, is a further example of the platform’s versatility in targeting the complex and numerous serotypes of botulinum toxin. It further underscores the platform’s potential for generating recombinant pAb drugs against emerging pathogens, toxins or high-priority biothreats.

What is the significance of GigaGen’s lead anti-hepatitis B candidate and what are the planned milestones for its clinical development?

Despite the availability of vaccines, HBV affects more than 296 million people worldwide, causing more than 800,000 deaths each year, and there is currently no cure for chronic hepatitis B. Available drugs can stop viral replication, but these drugs must be taken daily for life and the reduction of hepatitis B surface antigen (HBsAg), a major driver of HBV-related immune dysfunction and chronic disease, is limited. GigaGen’s hepatitis B candidate, GIGA-2339, is a first-in-class recombinant polyclonal therapeutic. It aims to eliminate HBsAg, support HBV-specific immune responses, and achieve functional cure. GigaGen aims to submit an Investigational New Drug (IND) application in 2024 and initiate clinical studies by 2025.