A solid Consortium project should contribute a unique and compelling approach to neuroblastoma and supply tools or components that enable other members of the Consortium to make their best work even better. The project detailed here commences with the selection and careful characterization of a dozen fully human antibodies to Glypican-2, the most promising antigen in neuroblastoma, from a pre-existing hybridoma stock. These antibodies, along with their full sequences, binding affinities, cellular internalization, epitope, and (where possible) crystal structures, will be made available to Consortium members within the first year for use in their modality of choice. This project will explore their utility as components in double bispecific antibody therapy: this double bispecific approach targets two cancer antigens and two T cell receptors simultaneously, inducing T cell activation and co-activation only in the presence of cancer cells expressing both antigens. The double targeting strategy should allow for a much higher level of selective engagement and killing than has heretofore been possible with therapies that target only a single cancer antigen, and should it prove effective in neuroblastoma the approach is likely to have utility in a wide variety of cancers. One historical weakness for the development of immuno-oncology approaches such as this one is that the animal models have had very little predictive value. For this reason, the best of the humanized mouse models, ?MISTRG? mice, will be used both for the development of these molecules and for testing the other consortium members? approaches, where they could be useful. CIVO multi- needle array technology will be employed to simplify the combinatorial challenge associated with testing pairs of bispecific molecules; this technology will also be open for use collaboratively with the other Consortium members. In short, the proposal provides the Consortium with human antibodies against a validated neuroblastoma target, access to the current state-of-the-art in humanized mice, a CIVO multi-needle array device to facilitate testing therapeutics, and a double bispecific antibody therapeutic approach that promises a high level of T cell killing and selectivity and a likely broad applicability beyond neuroblastoma.
This project will bring to the Consortium a dozen well-characterized, fully human antibodies against the neuroblastoma target Gypican-2, two novel in vivo immuno-oncology assay systems (CIVO and MISTRG mice), and a promising, double bispecific antibody therapeutic strategy. The antibodies and assay systems will be opened up for Consortium members for use in developing their therapeutic modalities of choice. The use of two bispecific molecules simultaneously should allow for a uniquely potent and selective targeting of neuroblastoma, and not only would the lead molecules be ready for the clinic, but success would demonstrate a generalizable approach to the treatment of almost any cancer, even those that fail to express a cancer-specific antigen.
