Oliver Seifert, a Scientist at the Institute of Cell Biology and Immunology, University of Stuttgart shared insights and perspective on engineering of multivalent antibody-scTRAIL by introducing different homodimerization modules leads to a novel platform of therapeutic molecules for cancer therapy, and discusses his upcoming presentation “Multivalent Antibody-TRAIL Fusion Proteins for Cancer Therapy” to be delivered at the 4th annual Fusion Protein Therapeutics conference in Boston.
Presentation | Tuesday, May 1, 2:05pm
Multivalent Antibody-TRAIL Fusion Proteins for Cancer Therapy
Oliver Seifert, PhD, Scientist, Institute of Cell Biology and Immunology, University of Stuttgart
Engineering of multivalent antibody-scTRAIL (single-chain derivatives of TRAIL) by introducing different homodimerization modules leads to a novel platform of therapeutic molecules for cancer therapy. Our results show that both tumor targeting and enhancing the valency of scTRAIL fusion protein provides enforced apoptosis induction together with good anti-tumoral activity and tolerance in vivo. Due to the modular composition of this novel platform, exchanging the specificity of the antibody moiety facilitates the treatment of a broad spectrum of different cancer entities.
Q. How can the antibody-single-chain derivate of TRAIL be used to fight cancer?
TRAIL is the abbreviation for TNF-related apoptosis inducing ligand and is expressed in the human body, for example on cytotoxic cells of the immune system. As the name already indicates, TRAIL is able to induce apoptosis to cells, which are somehow damaged and should be removed from the body. Interestingly, it is described in literature, that TRAIL efficiently induces apoptosis in transformed cells and leaves normal healthy cells untouched. Thus, this makes TRAIL as an ideal molecule for the treatment of cancer. By increasing the valency of TRAIL to an hexavalent molecule, we can report increased bioactivity compared to unmodified trivalent molecules. In addition, tumor-specific targeting of this hexavalent molecule further increased its bioactivity leading to increased induction of apoptosis on tumor cells in vitro.
Q. How well is the engineered multivalent antibody-scTRAIL tolerated in vivo?
In the last years, we performed many different xenograft tumor mice models using antibody-TRAIL fusion proteins. Besides bioactivity of antibody-scTRAIL fusion proteins, safety of the fusion proteins was also analyzed in tumor bearing mice. Damage of liver (ALT) and of pancreas (β-amylase) was tested in serum samples obtained from treated animals. No differences between treated groups (antibody-scTRAIL and also the non-targeted version) were observed concerning ALT and β-amylase activity compared to the control group. As the human TRAIL molecule (which was used in these studies) is also cross-reactive to mouse TRAIL receptors, these results revealed good safety properties for TRAIL fusion proteins in mice.
Q. How can the specificity of the antibody moiety be changed?
As the antibody-TRAIL molecules are composed of different modules (TRAIL, Fc-part, and targeting moiety), changing the targeting moiety of the molecule leads to different specificities of this fusion protein. Besides the generation of scFv-Fc-scTRAIL fusion proteins, whole antibodies, which were fused with scTRAIL derivatives, were generated. Different specificities were introduced for the antibody-TRAIL fusion proteins: EGFR, HER2, HER3, FAP, MCSP.
Q. What is the benefit of altering the specificity of the antibody moiety?
Different entities of tumors express different molecules on their surface, which can be used for a targeted tumor therapy. For example, HER2 is highly overexpressed on different types of breast cancer. Modifying the specificity of antibody-TRAIL fusion proteins allows specific binding of the antibody-TRAIL fusion protein to the respective tumor cells via the targeting moiety leading to an increased cell death induction on these cells.
Q. What are you looking forward to at the PEGS Summit?
The PEGS Summit provides excellent talks regarding the clinical as well as the pre-clinical treatment of cancer. Thus, being an attendee of PEGS provides precise and detailed insight into the field of targeted therapy for cancer using fusion proteins or bispecific (or multispecific) antibodies. Besides the attendance of the leading pharmaceutical companies, also the presence of academic groups makes PEGS an excellent summit for therapeutic approaches.
Oliver Seifert holds a PhD in Molecular Biology from the University of Stuttgart and he is a Post-Doc at the Institute of Cell Biology and Immunology based at the University of Stuttgart, Germany. Research interests focus on the design and development of bispecific antibodies and recombinant bifunctional molecules, including half-life extension strategies, for tumor therapy.