The IACT project (IACT = Immunostimulatory Agonist antibodies for Cancer Therapy; www.IACT-project.eu), is an international, collaborative effort supported by the European Commission 7th framework program that focuses on the clinical development of agonist IS-Abs targeting three complementary receptors on immune cells: CD40, OX40 and 4-1BB/CD137.
The IACT consortium provides the expertise and infrastructure required for the trials. The basis of IACT is formed by 4 European scientists with long-standing experience in the heart of the matter: agonist immunostimulatory Abs (IS-Abs). Prof. Martin Glennie (University of Southampton, UK) was the first to pioneer the efficacy of anti-CD40 IS-Abs agonist experimental tumors in mice and has since worked relentlessly towards the clinical translation of this concept to the clinic, resulting in the clinical anti-CD40 IS-Ab ChiLob7/4, which successfully went through phase I testing (ref), and the availability of clinical candidates for agonist IS-Abs that stimulate other immunostimulatory receptors, including OX40 and 4-1BB. Prof. Ignacio Melero (Pamplona, Spain), when working at pharma-company Bristol Meyers Squibb Inc. USA, pioneered the efficacy of anti-4-1BB IS-Abs against experimental tumors in mice and subsequently – upon his return to Spain - established a productive research line focusing on the 4-1BB pathway as well as an impressive lineup of clinical trials concerning IS-Ab. The research of Prof. Dr. Mario Colombo (Milan, Italy) features a long-standing interest in the OX40-pathway, which resulted in new insights that are essential for clinical implementation of these drugs Prof. Dr. Rienk Offringa, coordinator of the IACT program, was involved in the discovery that agonist anti-CD40 can mobilize anti-tumor T-cell immunity through activating antigen-presenting dendritic cells, and has successfully continued to work on the exploitation of this pathway, as well as the 4-1BB and OX40 pathways, for cancer immunotherapy. From 2007 – 2010 he worked at the biotech company Genentech Inc. USA on the clinical development of agonist IS-Abs targeting CD40 and OX40. Upon his move to Heidelberg in 2011, he used his experience in agonist IS-Ab drug development to set up the IACT consortium with the aim of boosting clinical translation of agonist IS-Abs for cancer immunotherapy in Europe.
Clinical centers and clinical trials
While the 4 academic partners cover the conceptual aspects of IS-Ab development in a highly complementary fashion, their associated clinical partners in Germany, the UK and Spain bring in not only the expertise with exploratory clinical studies, but also large patient cohorts that match the needs of IACT for performing the clinical studies. The main basis for the IAPACA trial will be the European Pancreas Center (EPC) in Heidelberg, one of the world’s largest and most advanced clinics for the surgical treatment of pancreatic cancer. The EPC is part of the Surgery Clinic of University Hospital Heidelberg, which is led by Prof. Dr. Markus Büchler, a widely renowned expert on pancreatic cancer. The pancreatic surgery is coordinated by Prof. Dr. Thilo Hackert, while the long-standing tissue biobanking program of the EPC is coordinated by Dr. Oliver Strobel. This biobanking program constitutes an important basis for the PD biomarker studies associated with the trial. Notably, Prof. Dr. Offringa holds appointments at both the German Cancer Research Center and at the Surgery Clinic, which are located at the same campus, thereby ensuring close knit interactions between research lab and clinic. Also located at the Heidelberg campus is the German National Cancer Institute (NCT), which provides standard of care non-surgical treatment, including chemotherapy, to a variety of cancer patients and is also the site at which many clinical studies – amongst others with checkpoint inhibitor IS-Abs – are taking place. Many of these trials are led by Prof. Dr. Dirk Jäger, co-director of the NCT and expert on the clinical testing and application of oncology and immunotherapy drugs. Studies concerning pancreatic cancer include Dr. Christoph Springfeld, a specialist in non-surgical treatment of this disease.
The second site for the trial will be the University Hospital Southampton (U.K.), involving three clinical researchers that have longstanding collaborative interactions with Prof. Glennie: Prof. Dr. Peter Johnson, Prof. Dr. Christian Ottensmeier and Dr. Emma King. Prof. Johnson has coordinated the recently concluded safety trial with anti-CD40 Ab ChiLob7/4 and is a member of the board of Cancer Research U.K. (CRUK) The latter is of great importance for the present trial, because anti-CD40 IS-Ab ChiLob7/4 is owned by Cancer Research technology (CRT), a subsidiary of CRUK, and because the clinical batch of anti-CD40 Ab will be produced by the Biotherapeutics Development Unity (BDU) of CRUK. Prof. Ottensmeier has a vast expertise in conducting cancer immunotherapy trials in different cancer indications, including the evaluation of treatment induced immune responses in cancer patients, and has also participated in the aforementioned safety trial. Dr. Emma King is the key clinician in Southampton with respect to the recruitment and treatment of pancreatic cancer patients and has been involved in multiple trials coordinated by Prof. Ottensmeier.
Notably, the Southampton team is the main driver of a second trial that is run by the IACT consortium, which involves application of anti-CD40 IS-Ab in conjunction of mRNA vaccination for the treatment of HPV16-positive head and neck squamous cell carcinoma (HNSCC; HARE-40 protocol), and which will involve the clinic in Pamplona, Spain as second site (University Hospital Navarra; Prof. Dr. Ignacio Melero and Dr. Jose Luis Peres Gracia). The rationale for this second trial is that striking pre-clinical results with agonist anti-CD40 Ab were not only obtained by combining these IS-Ab with gemcitabine (see above), but also by using these IS-Ab to enhance the efficacy of cancer vaccines. Pre-clinical studies demonstrated that anti-CD40 IS-Abs can strongly (>10-fold) increase the potency of antigen-specific vaccines. This second study will be staged in HPV16+ HNSCC and not in pancreatic cancer, because of the availability of suitable and safe vaccine antigens in the former, but not in the latter indication. Taken together, the two trials represent the two pre-clinical settings in which most striking anti-tumor efficacy of anti-CD40 IS-Abs have been observed, and are highly complementary in providing insight into the clinical potency of this drug concept.
The IACT consortium also includes 4 industry partners that bring in expertise and proprietary technology related to antibody engineering, drug development and cancer immunotherapy, on the basis of which a pipeline for the development of next-generation Ab-based drugs has been set up. SME-partner BioNTech RNA Pharmaceuticals GmbH (Mainz, Germany), led by cancer immunotherapy expert Prof. Dr Ugur Sahin, plays a critical role in the IACT clinical trial program, in that it generated the producer lines for the production of clinical-grade anti-CD40 Ab ChiLob7/4 (along with production of clinical-grade mRNA vaccine for the HARE-40 trial). In the context of this effort, a licensing agreement was concluded between CRT and BioNTech that supports further clinical development of ChiLob7/4, thereby creating a path for future clinical studies and commercial development of this drug.
SME-partner Glycotope (Berlin, Germany) has developed the proprietary technology GlycoExpress™ through which glyco-optimized Abs can be produced. GlycoExpress™ comprises a toolbox of proprietary, glyco-engineered human cell lines that differ in the expression of defined cellular enzymes involved in protein glycosylation. Consequently, production of IgGs by these cell lines results in IgG-batches with defined and distinct glycosylation profiles. The main aim of Glycotope’s effort in IACT will be to investigate the impact of said modifications on the agonist activity of IS- Abs, which is a so far unexplored area of research. Furthermore, human glycosylation by GlycoExpress™ cells allows the generation of recombinant IgG with glycosylation patterns that are highly comparable to the naturally occurring structures. Consequently, glyco-optimized IS-Abs are expected to display reduced immunogenicity as compared to their conventional counterparts. In order to maximize resemblance to natural human IgG-structure, the lead IS- Abs will be humanized.
SME-partner BioInvent (Lund, Sweden) will generate dual-specific agonistic IS-Abs of which each Fab arm interacts with two of our three target molecules, involving its proprietary n-CoDeR® antibody libraries (http://www.bioinvent.se/science/n-coder.aspx). These antibody libraries together contain 40 billion (4x10E10) human antibody genes. All the antibodies within a specific library have the same framework structure, which has low immunogenicity. However, each antibody has a unique combination of complementarity determining regions (CDRs) that defines its antigen binding specificity. These CDRs were originally isolated from the antibodies of a large number of human donors and, using the n-CoDeR® technology, recombined into new antibody molecules. The unique recombination process allows the libraries to contain a wider variety of antibodies than could have been created naturally by the human immune system, including human-reactive antibodies. This means that there is a higher likelihood of finding antibodies with high affinity and high specificity against a particular target.
SME-partner Leadartis (Madrid, Spain) will exploit the notion that immune receptors need to be clustered in order to trigger immune cell activation, implying that Ab molecules with a higher valency are likely to be more potent agonists by crosslinking receptor molecules more efficiently. In view of this Leadartis, a preclinical stage biotechnology company developing multivalent Abs, will employ its proprietary Trimerbody™ technology to develop IS-Abs. Of special interest within the IACT project is the trivalent configuration from the perspective that the receptors concerned, all members of the TNFR- family, are known to trimerize upon binding of their natural, trimeric ligand. Consequently, trivalent IS-Abs will not only feature increased avidity to their target compared to conventional IgG Abs, but may also be a better mimic of the natural receptor ligands.