Figure provided by Dr. Damian Green
Non-Hodgkin lymphoma is a cancer affecting immune cells such as natural killer cells, B or T lymphocytes and is the most common form of lymphoma. Twenty five percent of the patients do not survive the disease, leading to the death of 19,790 Americans in 20151. Pretargeted radioimmunotherapy (PRIT) has been explored as a means of directly delivering radiation to the cancer cells. This strategy uses antibodies that bind specifically to the targeted cancer cells and deliver radionuclides, attached to the antibodies, that will directly kill the cancer cells. First generation, directly radiolabeled antibodies, known as radioimmunotherapy (RIT) has proven efficient against Non-Hodgkin B cell lymphoma, with two radioimmunotherapeutic agents being FDA approved. However, the handling of radioactivity logistically complicates the procedure. As a consequence, radioimmunotherapy has not become the widespread success one would expect for such a promising strategy. Improving the efficacy while minimizing the toxicity would make it more appealing.
Prior antibodies successfully used in PRIT have been coupled to a streptavidin protein whose ligand, the biotin, also exists in untreated human cells. Therefore, administering radiolabeled biotin to the patient for radionuclides delivery to streptavidin-labeled antibodies attached to the cancer cells does not prevent the unlabeled endogenous, or natural, biotin in cells from also binding to the antibody and attenuating the treatment. A second issue is that the streptavidin is of bacterial origin and therefore generates an immune response. Dr. Damian Green's laboratory in collaboration with Dr. Oliver Press and his team (Clinical Research Division) have engineered a bispecific antibody that does not rely on streptavidin and biotin, eliminating concerns about natural biotin competition and reducing the immune response. A bispecific antibody is an artificial antibody combining the specificities of two different antibodies. The bispecific antibody can simultaneously bind to the targeted cancer B cell and to the radiolabeled isotope (illustrated in the figure above). In their recent publication in Cancer Research, Green and Press compared the efficiency between this newly engineered bispecific antibody and the streptavidin/biotin-coupled antibody to target the CD20 antigen expressed by non-Hodgkin B-cell lymphoma.
Experiments were performed in immunocompromised mice, which is advantageous because it allows the development of human tumors without rejection by the immune system. After optimization, the bispecific antibody showed significant specific binding to the tumor cells. Following these encouraging results, the impacts of the two antibodies on tumor growth and on long-term survival were analyzed. Untreated tumor bearing mice died within 25 days, while 60-70% of the mice treated with the same dose of either the streptavidin/biotin antibody or the bispecific antibody survived for the five month duration of the experiments. In this comparison, the two types of antibodies were similarly efficient.
However, since the streptavidin/biotin antibody possesses twice as many binding sites for the radiolabeled compound than the bispecific antibody, the researchers evaluated whether administering twice as much bispecific antibody would compensate for the difference and enhance the radiolabeled element's binding capacity and therapeutic efficacy. Indeed, in these conditions 90 to 100% of the bispecific antibody-treated mice survived, which is twice as efficient than the established dose of the streptavidin/biotin antibody. Finally, assessment of toxicity (weight loss, metabolite levels, blood cell counts) indicated the superiority of the bispecific antibody on overall health relative to the streptavidin/biotin antibodies.
These data are very promising for future use of bispecific antibodies in PRIT. "We are actively studying this bispecific approach in other hematologic (blood cell) malignancies as well" said Dr. Green, who also presented very encouraging findings detailing their work using an anti-CD38 bispecific antibody in multiple myeloma during an oral abstract talk at the American Society of Hematology meeting last December2. "Drs. Orozco and Press also have promising data using a similar approach in myeloid leukemia models", stated Dr. Green, who also indicated that his team is now hoping to use these very promising findings to secure funding (donor and grant support) to move this approach to the clinic quickly. "To that end, we are exploring ways to scale up production of the bispecific fusion antibodies for human clinical trials. In addition, we are investigating potential synergy of PRIT with other agents (e.g. ibrutinib, navitoclax, idelalisib) in lymphoma and a role for bispecific PRIT in stem cell transplantation", concluded Dr. Green.
Funding for this research was provided by the National Institutes of Health and by the David and Patricia Giuliani Family Foundation.
Green DJ,Frayo SL,Lin Y,Hamlin DK,Fisher DR,Frost SH,Kenoyer AL,Hylarides MD,Gopal AK,Gooley TA,Orozco JJ,Till BG,O'Steen S,Orcutt KD,Wilbur DS,Wittrup KD,Press OW. 2016. Comparative analysis of bispecific antibody and streptavidin-targeted radioimmunotherapy for B cell cancers. Cancer Research. Epub ahead of print.
1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. 2015. CA: A Cancer Journal for Clinicians. 65:5-29.
2 Green DJ, Jones JC, Lin Y, Frayo SL, Kenoyer AL, O'Steen S, Peters A, Frost SHL, Orozco JJ, Gopal AK, Hylarides MD, Fisher DR, Sandmaier BM, Till BG, Balkin ER, Hamlin DK, Wilbur DS, Orcutt KD, Wittrup KD, Press OW. 2015. A Novel Bispecific CD38 Antibody Eradicates Multiple Myeloma in a Mouse Model Following Yttrium-90-DOTA Capture. Blood. 126:118.