Cancer development is accompanied by the generation of evasion mechanisms, hiding the tumor cells from the immune system. The challenge of cancer immunotherapy consists in resolving this unfavorable situation by activating and directing our defense system to eliminate the tumor. Key features therefore are not only the specific recognition of the tumor cells by the immune cells, but also the generation of appropriate surrounding conditions for the development of an efficient antitumor immune response. This can be addressed by focusing on the complex network of ligands/cytokines and corresponding receptors that regulate the immune system. Amongst others, members of the B7/CD28-superfamily, TNF/TNFR-superfamily and cytokines/common γ-chain receptor family have shown great antitumor potential. We are interested in exploring how tumor-directed delivery and defined combination of such molecules can impact the therapeutic potential.
Targeted strategies with antibody-fusion proteins
Tumor targeting can be achieved by antibodies binding specifically to tumor associated antigens. This property makes recombinant antibodies a valuable tool for diverse targeted approaches. For example, bispecific antibodies can retarget effector cells to tumor cells, inducing artificially an antitumor immune response. Also, ligands or cytokines fused to recombinant antibodies can be directed to and presented at the tumor cell surface to immune cells, modulating their response. In order to improve the efficacy of such molecules at the tumor site we design antibody fusion proteins, focusing either on optimized presentation or a combined mode of action, analyzing their effect on immune cell populations in vitro and their antitumor potential in mouse models in vivo.
Selected research articles
- Sapski S, Beha N, Kontermann R, Müller D. (2017) Tumor-targeted costimulation with antibody-fusion protein improves bispecific antibody-mediated immune response in presence of immunosuppressive factors. OncoImmunology 6(12):e1361594.
- Fellermeier S, Beha N, Meyer JE, Ring S, Bader D, Kontermann RE, Müller D (2016) Advancing targeted costimulation with antibody-fusion proteins by introducing TNF superfamily members in a single-chain format. OncoImmunology 5(11):e1238540.
- Kermer V, Hornig N, Harder M, Bondarieva A, Kontermann RE, Muller D. (2014) Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. Mol Cancer Ther. 13(1):112-21.
- Hornig N, Reinhardt K, Kermer V, Kontermann RE, Müller D. (2013) Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. Cancer Immunol Immunother. 62(8):1369-1380.
- Hornig N, Kermer V, Frey K, Diebolder P, Kontermann RE, Müller D. (2012) Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. J Immunother. 35(5):418-29.
- Kermer V, Baum V, Hornig N, Kontermann RE, Müller D. (2012) An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site. Mol Cancer Ther 11: 1279-1288.
- Müller D, Frey K, Kontermann RE (2008) A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother. 31(8):714-22.
- Müller D (2015) Antibody fusions with immunomodulatory proteins for cancer therapy. Pharmacol Ther. 154:57-66.
- Müller D (2014) Antibody fusion proteins for cancer immunotherapy: an update on recent developments. BioDrugs. 28(2):123-31.
- Müller D (2012) Targeted cancer immunotherapy: mimicking physiological trans-presentation of IL-15. OncoImmunology 1(7):1213-1214.
- Müller D, Kontermann RE (2010) Bispecific antibodies for cancer immunotherapy: Current perspectives. BioDrugs. 24(2):89-98.
- Muller D, Kontermann RE (2007) Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr Opin Mol Ther. 9(4):319-26.
- Siegemund M, Beha N, Müller D. (2018) Production, Purification, and Characterization of Antibody-TNF Superfamily Ligand Fusion Proteins. In: Antibody Engineering, Methods and Protocols. 3th D. Nevoltris and P. Chames (Eds.), Springer Nature, New York, pp.351-364.
- Müller, D. and Kontermann, R.E. (2014) Bispecific Antibodies In: Handbook of Therapeutic Antibodies. 2th Dübel S. (Hrsg.), WILEY-VCH Verlag, Weinheim. Vol.I pp.267-293
- Müller, D. & Kontermann, R.E. (2011) Recombinant bispecific antibodies for cancer therapy. In: Antibody Expression and Production (Cell Engineering 7), Al-Rubeai M. (Ed.), Springer-Verlag, Heidelberg, pp.235-250.
- Müller, D. & Kontermann, R.E. (2011) Diabodies, single-chain diabodies and their derivatives. In: „Bispecific Antibodies“, Kontermann R.E. (Ed.), Springer-Verlag, Heidelberg, pp. 83-100.
- Müller D & Gerspach J (2010) Antibody-Cytokine Fusion Proteins with Members of the TNF-Family. In: Antibody Engineering R Kontermann and S. Dübel (eds.) Springer-Verlag Berlin Heidelberg. Vol.2 pp. 113-126.
Applications of students and scientists interested in biomedical engineering and cancer immunotherapy are always welcome! Please send your CV and a short summary of your research interests to Dr. Dafne Müller