Vaccines That Induce Antibodies
A large-scale immunohistology screen was initiated by the group of physician-scientist Philip O. Livingston to identify the dominant cell-surface antigens expressed by common human cancers. A series of studies was conducted in mice and in patients to identify the most-potent vaccines for inducing antibodies against these antigens.
In every case, the best antibody response was induced by covalently linking the antigen to the large carrier molecule keyhole limpet hemocyanin (KLH), which is obtained from the keyhole limpet, a mollusk. The optimal adjuvants were purified saponin fractions or semisynthetic saponins, all derived from the bark of a South American tree.
These vaccines have induced consistent antibodies against a series of cell-surface carbohydrate and protein antigens including GM2, GD2, GD3, fucosyl GM1, and sialyl Lewis a (also known as CA19.9) gangliosides; the neutral glycolipid globo H; blood-group-related antigens Tn, sialyl Tn, and Thompson Friedenreich antigen (TF); and mucin 1 (MUC1).
More recently, in work performed by Memorial Sloan-Kettering’s Clinical Grade Production Facility, these individual monovalent vaccines have been combined into polyvalent vaccines containing three to seven different conjugates. A series of phase II clinical trials in patients with ovarian cancer, sarcoma, and neuroblastoma was designed to determine whether vaccine-induced antibodies against multiple cell-surface antigens are able to prolong disease-free survival and overall survival after surgical resection or chemotherapeutic response of all known disease.
These studies include ongoing, multicenter, randomized trials in ovarian cancer patients who are in second complete remission, and stage IV sarcoma patients who have been treated with surgery. Human monoclonal antibodies are prepared from the B cells of these immunized patients in collaboration with MabVax Therapeutics, Inc.
Antitumor and anti-infectious disease vaccines require adjuvants in order to obtain optimal immunogenicity and therapeutic and protective efficacy. There are few adjuvants available for clinical use that have sufficient potency and acceptable toxicity levels.
QS-21, a natural saponin isolated from the bark of Quillaja saponaria, significantly outperforms other adjuvants in eliciting productive antibody and T cell responses. It has remained the adjuvant of choice in many vaccine trials of cancers, infectious diseases, and degenerative disorders. However, there are several problems associated with the use of QS-21 as an adjuvant, including its scarcity, dose-limiting toxicity, and chemical instability.
In collaboration with the laboratory of chemist David Y. Gin, and more recently with the groups of chemist Derek Tan and radiochemist Jason S. Lewis, we have developed a series of synthetic and semi-synthetic saponin molecules with improved purity, availability, and stability and with diminished toxicity. The impact of these semi-synthetic QS-21 analogues on serologic responses after vaccination with a variety of antigens is now being compared in murine models.
Ongoing Projects in Dr. Ragupathi’s Laboratory
- Stability and related FDA-required quality control testing is ongoing for the vaccines currently in multi-center Phase II trials.
- Collaborating with chemist Samuel Danishefsky, we are testing a series of unimolecular polyvalent antigen constructs. A clinical trial with the initial unimolecular polyvalent construct is ongoing in ovarian cancer patients. Investigations into class, subclass, and functional characteristics of polyvalent vaccine-induced antibodies, as well as the correlation of these responses to clinical outcome, are under way.
- We are evaluating a series of fully human monoclonal antibodies derived from our vaccinated patients to define their CDC and ADCC activities in vitro, and the ability of these antibodies to protect from tumor challenge in vivo in xenograft models.
- We are also exploring approaches to further increase the efficacy of vaccine-induced antibodies and administered monoclonal antibodies in these murine models, focusing on combinations with chemotherapy — especially with inhibitors of the PI3K pathway.
- We are testing the impact of selected synthetic QS-21 analogues on immune responses to a range of carbohydrate and peptide antigens targeting cancer as well as malaria, Lyme disease, and other infectious diseases.
- Since the mechanism of action of QS-21 and the analogues is largely unknown, we are collaborating with Jason Lewis and Derek Tan to utilize semi-synthetic labeled QS-21 analogues synthesized with labels to understand the biodistribution and mechanism of action of QS-21, and how different portions of the QS-21 molecule contribute to adjuvant activity and toxicity.