iRASP: a novel platform to design efficacious cancer targeted immunotherapies

Since the approval of rituximab, antibody-based immunotherapies have dramatically changed the natural history of several cancer types. However, due to the paucity of viable tumor antigens discovered by the standard target-first approach, only a few antibody-based drugs have entered into clinical use. Furthermore, more than 50% of the available therapeutic antibodies target only five antigens, and consequently no targeted immunotherapeutic option exists for the majority of cancer types. Therefore, it has become of pivotal importance to design immunotherapies against novel tumor-associated antigens efficacious in halting currently untreatable tumors.

The target-first approach involves the discovery of tumor-specific antigens from high-throughput RNA- and DNA-sequencing data, or protein-based methodologies. Such strategy allows optimal tumor antigen specificity due to dataset analyses, however the in vivo accessibility of tumor antigens remains uncertain and cannot be easily predicted. Additionally, such approach does not take into account a variety of post-translational modifications, which can either generate novel epitopes or mask the expected antigenicity.

Alternative to the target-first approach is the antibody-first strategy, which allows to unbiasedly identify tumor-specific antibodies, without prior knowledge of their target antigens. The inventors developed a unique platform, named iRASP (in vivo Recombinant Antibody-Screening Platform), that relies on antibody phage display libraries, in vivo screenings and next generation sequencing (NGS) to discover new therapeutic antibodies for cancer patients. It is a fast and cost-effectiveness platform that allows to in vivo isolate tumor-binding phage antibodies directly from tumor-bearing mice, and then shortlist the selected in vivo tumor-binders on the basis of the tumor specificity, thanks to a reliable and robust prioritization process. As a proof of concept (funded by ERC PoC grant), a few independent iRASP based candidates were isolated showing strong anti-tumor effect against both blood and solid untreatable tumors.

Applications:
iRASP platform can be tailored and applied to virtually any tumor type, starting from different phage display libraries, for the design of novel antibody-based immunotherapies (i.e naked therapeutic antibody, immuno-cytokine, bispecific antibody or CAR-T).

Advantages:
New antibodies can be in vivo selected against patient-derived xenografts (PDXs) without prior knowledge of target antigen, and can be in vitro engineered to boost their tumoricidal potential or tumor-targeting ability. This approach provides the advantage of immediately generating a viable tumor specific antibody that can be directly tested in vivo. 

IP RIGHTS: 
PCT/EP2019/066217
Owners: IEO