Since the approval of the first monoclonal antibody “rituximab”, 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 few antibody-based drugs have entered into clinical use, being able to help only a fraction of all cancer patients.
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 intractable tumors.
The total addressable market of iRASP platform is the global cancer immunotherapy market, anticipated to reach
the market value of USD 170.7 B by 2028. In line with this prevision, immunotherapy is forecast to become the
oncology treatment of choice by 2026, with an estimated 60% of previously treated cancer patients likely to adopt
immunotherapy in this timeframe. iRASP platform has been designed to target oncological indications with high
unmet need, particularly intractable tumors poorly respondent or resistant to the standard of care and also rare
tumors for which standard of care do not even exists. In this perspective, iRASP has been successfully exploited
against refractory T-cell Acute Lymphoblastic Leukemia (T-ALL) and Acute Myeloid Leukemia (AML), two oncological indications with high unmet clinical need and both qualified as rare diseases.
The success of targeted immunotherapies lies in the balance between clinical efficacy, which strictly depends on in vivo accessibility of the tumor-associated target antigen, and toxicity, which instead depends on its preferential expression by tumor cells. Immunotherapies raised against ubiquitously expressed antigens or promiscuous epitopes are at risk of high toxicity, thereby limiting clinical efficacy. On the other hand, immunotherapies against cancer-specific antigens, if poorly expressed or not accessible, are expectedly at risk of low efficacy. The target-first approach typically used for antibody development starts from 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, thereby limiting the in vivo clinical efficacy of the antibodies.
Current technology limitations
Due to the paucity of tumor-specific antigens discovered by the standard target-first approach, the creation of robust immunotherapies has remained frustratingly limited, leaving most tumors treatable by only chemotherapeutic or radiological regimens. Many companies developing new antibody therapies, focus their business on library-based methods coupled with in vitro antibody discovery processes against already-known tumor antigens. However, this approach makes difficult to predict the functional in vivo antigenicity of the targets and often results in poorly effective treatments. Similar limitations also distinguish the function-first approach exploited by other companies, by which new antibodies are identified without prior knowledge of their target antigens, but based on their in vitro and not in vivo tumor-binding ability. As a matter of fact, there are no current immunotherapeutic options relying on antibodies obtained from in vivo screenings and iRASP is the unique platform that will provide this solution.
As a proof of concept, three iRASP-based immune-cytokines were generated, showing strong anti-tumor effect against refractory human T-cell acute lymphoblastic leukaemia (T-ALL). The further development of iRASP platform focuses on the discovery and in vivo validation of new therapeutic antibodies against acute myeloid leukemia (AML), for which there are no effective treatments. Thanks to the large collection of patient-derived xenograft (PDX) available at IEO for the in vivo screenings, we envisage to exploit our innovative approach to design novel efficacious immunotherapies for several intractable tumors. Our platform, by combining the in vivo screening with the robust prioritization process, enables the circumvention of issues inherent to standard methodology, and is likely to provide clinically effective antibodies representing a solid, commercially-exploitable product.
Our technology and solutions
We have developed an innovative in vivo Recombinant Antibody-Screening Platform (iRASP) that relies on the antibody-first strategy. This strategy uses unbiased, phenotypic screening to select tumor-specific antibodies, without prior knowledge of their target antigens. Specifically, iRASP integrates a novel in vivo phage display screening, by which the antibody phage libraries are directly injected into tumor-bearing mice, with a reliable and robust prioritization process that allows to isolate phage antibodies against true tumor-associated antigens and shortlist them on the basis of their relative frequency and specificity for tumor cells. It is a fast and cost-effective platform that can be tailored and applied to virtually any tumor type for the design of new and effective immunotherapies for cancer patients, and it allows to identify both new therapeutic antibodies and their tumor-associated targets.
Great potential application: iRASP platform can be adapted to virtually any tumor type to isolate phage antibodies that can be in vitro engineered to boost their tumor-targeting ability and tumoricidal potential. iRASP-based candidates may be used as naked therapeutic antibodies or conjugated with cytotoxic moieties or even adapted for CAR-T cell therapy. Specifically designed for the discovery of new therapeutic antibodies, iRASP might be also exploited for diagnostic or theragnostic applications in oncology. Focus on in vivo screenings: iRASP relies on in vivo screenings on both tumor and healthy tissues, allowing to isolate only true tumor-binding antibodies that do not in vivo cross-react with normal cells. This is also obtained thanks to the in vivo bio-localization step of the phage candidates, previously isolated from patient-derived xenograft (PDX) models.
Identification of novel targets: iRASP allows to discover new tumor antigens endowed with validated antigenicity, providing not only new therapeutic antibodies, but also novel targets for cancer immunotherapy.
Currently, our pipeline consists of three validated T-ALL immune-cytokines, whose target antigens are under investigation. By the end of 2021, we plan to enrich our portfolio with up to three antibodies in vivo validated against AML and start the proof of concept studies for additional candidates isolated against oncological indications with high unmet medical need, such as triple-negative breast cancer (TNBC), metastatic melanoma and non-small cell lung cancer (NSCLC). Accordingly, our current IP position, covering the platform and the first three T-ALL candidates, will be strengthened by filing new composition of matter patents claiming the new antibody candidates, after their in vivo validation. We are now seeking partners interested in further exploiting the iRASP platform through the creation of a dedicated start-up focused on discovery of new therapeutic antibodies for intractable tumors.
iRASP platform has been validated through the isolation of three independent antibodies endowed with tumor-binding ability, high specificity and strong anti-tumor effect against refractory human T-cell acute lymphoblastic leukaemia (T-ALL). In vivo proof of concept data demonstrate that the selected T-ALL candidates are therapeutically effective both as bare antibodies or antibody-cytokine fusions (immune-cytokines). Thanks to iRASP, new candidates have been isolated in other five oncological indications with high unmet medical need, including acute myeloid leukemia (AML) that remains the most lethal of human leukemias. The inventors are now engaged in the (i) further characterization and preclinical development of the three validated T-ALL antibodies and (ii) in vivo proof of concept studies of two candidates recently isolated against AML. iRASP platform and the three T-ALL candidates have been covered by a European patent application (EP18178526.2), internationally extended in December 2019 (PCT/EP2019/066217). The current Technology Readiness Level (TRL) is 4 (technology validated in the laboratory)