Research Area 2: Targeted antibody therapy

Project E

Gene Center and Department of Biochemistry, Ludwig-Maximilians Universität München

Heads: Prof. Dr. rer. nat. Karl-Peter Hopfner

Contact: hopfner(at)genzentrum.lmu.de

under construction

Project F

Dr. von Hauner Children’s Hospital, Klinikum der Universität München

Heads: Prof. Dr. Christoph Klein

Contact: christoph.klein(at)med.uni-muenchen.de

Projects within i-Target

• Project F: Identification and molecular validation of novel tumor antigens in pediatric neoplasms.

  Brief description: A new era of clinical medicine will take genomic and proteomic traits into consideration. We wish to define tumor-specific aberrations of the glycoproteome and to design novel tools for therapeutic purposes.

Methods:

Glycoproteomic mass-spectroscopy studies; Modeling of tumor-specific glycoproteins and generation of specific antibodies; Engineering of antibodies and in vitro testing

 The interdisciplinary project will be carried out in collaboration with Professor Josef Penninger (Vienna/Vancouver) and Karl Peter Hopfner (Gene Center)

Selected publications

1. Sradlmann J, Taubenschmid J, Wenzel D, Gattinger A, Dürnberger G, Dusberger F, Elling U, Mach L, Mechtler K, Penninger JM. 

   Comparative glycoproteomics of stem cells identifies new players in ricin toxicity.

   Nature 2017; 28 (7673): 538-542

2. Wirnberger G, Zwolanek F, Stadlmann J, Tortola L, Liu SW, Perlot T, Järvinen P, Dürnberger G, Kozieradzki I, Sarao R, De Martino A, Boztug K, Mechtler K, Kuchler K, Klein C, Elling U, Penninger JM.

   Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

   Nat Genet. 2014; 46 (9): 1028-33

3. Boztug K, Järvinen PM, Salzer E, Racek T, Mönch S, Garncarz W, Gertz EM, Schäffer AA, Antonopoulos A, Haslam SM, Schieck L, Puchałka J, Diestelhorst J, Appaswamy G, Lescoeur B, Giambruno R, Bigenzahn JW, Elling U, Pfeifer D, Conde CD, Albert MH, Welte K, Brandes G, Sherkat R, van der Werff Ten Bosch J, Rezaei N, Etzioni A, Bellanné-Chantelot C, Superti-Furga G, Penninger JM, Bennett KL, von Blume J, Dell A, Donadieu J, Klein C. 

   JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.

   Nat Genet. 2014; 46 (9): 1021-7

Project G

Department of Internal Medicine V, Friedrich-Alexander Universität Erlangen-Nürnberg

Heads: Prof. Dr. Andreas Mackensen and Prof. Dr. Dimitrios Mougiakakos

Contact:andreas.mackensen(at)uk-erlangen.de & dimitrios.mougiakakos(at)uk-erlangen.de

Goals and research areas

1. Optimization and development of T cell-based immunotherapies against cancer.
2. Immunoregulatory cells in malignant diseases and stem cell transplantation
3. Tumor metabolism and its impact on immune responses
4. Development of innovative metabolic targeting in cancer

Methods:

Our groups employ a broad range of immunological, molecular and biochemical techniques. We have a strong translational focus and interconnection with clinics is very strong. Access to state-of-the-art equipment within brand-new laboratories is granted including amongst others 12-color flow cytometry, laser-scanning microscopy and metabolic flux analyzers.

Projects within i-Target

• Project G: Induction of anti-leukemic T cell responses by bystander killing of CD33+ myeloid-derived suppressor cells (MDSC) via an anti-CD33 x anti-CD3 bispecific BiTE antibody construct. 

  Brief description: In recent years myeloid derived suppressor cells (MDSCs) have emerged as a key cell subset that promotes tumor immune escape. Strategies to overcome MDSC-mediated immune suppression hold promise to improve efficacy of modern immunotherapies. The aim of this PhD project is to (1) characterize MDSCs in patients with acute myeloid leukemia (AML) in order to (2) target them with a novel so-called CD33/CD3 bi-specific antibody (AMG330) showing a high anti-leukemic activity. In doing so we hope elicit two critical hits against AML. The methods utilized in this translational project will comprise a broad variety of cellular, molecular, and immunological techniques. 

Selected publications

1. Jitschin R, Hofmann AD, Bruns H, Gießl A, Bricks J, Berger J, Saul D, Eckart MJ, Mackensen A, Mougiakakos D:
   Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia:
   Blood 2014; 123 (17):2663-72.
2. Aigner M, Feulner J, Schaffer S, Kischel R, Kufer P, Schneider K, Henn A, Rattel B, Friedrich M, Baeuerle PA, Mackensen A, Krause SW:
   T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct.
   Leukemia 2013; 27:1107-15.
3. Mougiakakos D, Jitschin R, von Bahr L, Poschke I, Gary R, Sundberg B, Gerbitz A, Ljungman P, Le Blanc K:
   Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation.
   Leukemia 2013; 27 (2):377-88.
4. Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K: The impact of inflammatory licensing on the heme oxygenase-1 mediated induction of regulatory T-cells by human mesenchymal stem cells.
   Blood 2011; 117:4826-35.
5. Fischer K, Voelkl S, Berger J, Andreesen R, Pomorski T, Mackensen A:
   Antigen recognition induces phosphatidylserine exposure on the cell surface of human CD8+ T cells.
   Blood 2006; 108:4094-101.