First in Human Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Bispecific CD276xCD3 Antibody CC-3 in Patients With Colorectal Cancer

Metastasized CRC is an aggressive malignant disease with poor prognosis after failure of at least three lines of previous therapy, with an accordingly high medical need for new therapeutic approaches. Except for the small population with microsatellite instability, so far no relevant progress has been achieved in CRC by immunotherapeutics. CC-3 is designed to direct T cells towards CRC tumor cells and additionally reacts with tumor vessels. If successful, the trial establishes a novel type of dual anti-cancer action by also attacking tumor blood supply and allowing for improved influx of immune effector cells and thus holds promise as a new concept of immunotherapy for cancer patients.

The rationale for the therapeutic use of CC-3 is based on its proposed mode of action as a bsAb being specifically designed to direct T cells via its CD3 binding part towards tumor target cells via its CD276 binding part. Furthermore, CC-3 also reacts with tumor vessels of CRC thereby allowing for a dual mode of anti-cancer action by also attacking tumor blood supply and allowing for improved influx of immune effector cells. Due to its unique ability to redirect T cells via CD3 for CD276 expressing tumor cell lysis, CC-3 can elicit repeated target cell elimination by cytotoxic T cells and a polyclonal response of previously primed CD4+ and CD8+ T cells. Compared to other immunotherapeutics presently being approved or in development (bsAbs with alternative formats like the authorised bsAb blinatumomab or other antibodies or CAR T cells), CC-3 is expected to offer the following major advantages:

(i) reduction of side effects due to its optimal bsAb format and choice of TAA, which will allow for application of truly effective bsAb doses and accordingly increased efficacy; (ii) CD276 enables dual targeting, thereby improving accessibility of CRC tumors to immune effector cells, as prerequisite for therapeutic success (iii) CC-3 is an "off the shelf drug" eliminating the preparative work required for CART cell generation that delays treatment; (iv) the introduction of the YTE modification will allow for prolonged half-life an thus convenient dosing scheme

Clinical trial rationale with regard to objectives and further development of CC-3

In nonclinical studies, in vitro and in vivo, proof of concept, preliminary pharmakokinetic (PK) and pharmakodynamic (PD) effects as well as toxicology have been evaluated as described in detail in the IB . However, due to differences between animal models and the human situation, some aspects have to be assessed and further characterised in humans. For example, the target mediated drug disposition (TMDD), an effect that largely influences the serum half-life of antibody molecules particularly at low concentrations, cannot be properly addressed in mice. Similar problems arise with the YTE modification, which prolongs serum half-life of antibodies in humans but not in mice.Furthermore, non-human primates (NHP) and rodents have several limitations as predictive models for toxicity and immunogenicity evaluation of CC-3. The CD3 binding part of CC-3 does not cross-react with CD3 of macaques and thus it is not possible to evaluate in these NHPs dose limiting side effects. Therefore, a First in Human clinical trial is planned for CC-3 to characterise the effects of CC-3 in humans. In general CD276 is a target antigen with particularly attractive properties. It is expressed not only on tumor cells but also on tumor vessels, allowing for "dual targeting" of a variety of solid tumors including (but not limited to) GI cancer. The importance of vascular targeting for treatment of solid tumors has been elegantly demonstrated in numerous reports.