Excelimmune is creating a platform for developing human recombinant polyclonal antibody (HRPA) therapeutics, the next generation of antibody technology in the therapeutic arena.

Background

The immune system produces proteins called antibodies that help detect and neutralize foreign materials and pathogens (such as bacteria) that enter the body. It has long been established that supplying a patient suffering an infection with the right antibodies can aid in the recovery process.

The evolution of antibodies as a treatment began with the use of immunoglobulins, which are essentially concentrated antibodies found in the blood of a human donor. Purified from the blood of individuals with apparent immunity against a particular pathogen, the antibodies are injected into a patient suffering from an infection by the same pathogen.

Unfortunately, the technique of using donor immunoglobulin had several drawbacks. First, because immunoglobulin is derived from human donors rather than from animals or mass-production processes, it is not always readily available in the needed quantities, and is expensive. In addition, only a small percentage of the antibodies given to the patient are likely to specifically target the pathogen in question. Lastly, though perhaps most importantly, a considerable risk of contamination is associated with immunoglobulin, since it is derived from blood and plasma.

Addressing some of these limitations was the next generation of antibody therapy — monoclonal antibodies. A monoclonal antibody is specific for one target, can be manufactured in large quantities, and does not pose the contamination issues associated with immunoglobulin use. However, monoclonal antibodies can be associated with other issues. Pathogens such as bacteria and viruses, as well as cancers, are constantly evolving due to selection pressures. As a result, patients may experience monoclonal antibody therapy resistance as the disease continues to evolve. Additionally, administration of monoclonal antibodies to patients can cause severe immune reactions as the patient’s body reacts to the large quantity of monoclonal antibodies being introduced. Also, being recognized as a foreign protein, monoclonal antibodies can cause the patient’s immune system to develop antibodies against the monoclonal, causing the monoclonal antibodies to be removed from the patient’s body more quickly upon re-administration. This attenuated efficacy means that monoclonal antibodies may be of limited use against long term disease with multiple recurrences, like cancer. Lastly, most currently available monoclonal antibodies are artificial constructs that do not correspond to an exact analog naturally occurring in humans. This may limit their effectiveness and can cause dangerous side effects, since the antibody has not been vetted by the immune system’s filters against so-called self antigens. Fully human antibodies, by contrast, are more likely to be effective, since they serve to keep their hosts alive.

The latest chapter in antibody therapy, called human recombinant polyclonal antibodies (HRPA), avoids these drawbacks and provides a combination of the benefits of both immunoglobulin and monoclonal antibody therapy. Polyclonal antibody treatment consists of multiple antibodies against the same pathogen. This therapy is less prone to encounter resistance from pathogens and patients’ immune systems—the pathogens are less likely to become resistant to the multiple antibodies in HRPA and the relatively lower concentration of each antibody in the polyclonal mixture reduces the potential toxicity of HRPA treatment, and reduces the potential for the patient’s immune system to develop antibodies against the HRPA. HRPA also overcomes the challenges of infection transmission and limited production, since it can be manufactured outside of the human body. And, being fully human, HRPA are more likely to be effective and less likely to cause side effects than artificially constructed antibodies.