Biology subjects

Dietze, K. A.

Publications and source records attributed to Dietze, K. A..

3 recordsLinked to original sources

bioRxiv2025

A novel sweeping antibody exhibits efficient clearance of the cancer- and autoimmunity-associated cytokine interleukin 16

Targeting soluble antigens using conventional monoclonal antibodies is challenging due to high levels of antigen and limited antigen clearance per antibody molecule. Sweeping antibodies are engineered monoclonal antibodies that more efficiently clear soluble antigens than conventional antibodies. Sweeping antibodies contain two modifications: (1) pH-dependent antigen binding to facilitate lysosomal degradation of the targeted antigen while allowing antibody recycling and (2) enhanced neonatal Fc receptor (FcRn) engagement, resulting in 50-1,000-fold increased clearance of target antigen compared to conventional antibodies. The pleiotropic cytokine interleukin 16 (IL-16) has been proposed as a promising therapeutic target for monoclonal antibody therapy, due to its high expression and potential disease-promoting function in autoimmune diseases and cancer. Here, we develop the first fully human antibody as well as multiple sweeping antibodies targeting IL-16. We demonstrate that amenability to the introduction of pH-dependent binding into anti-IL-16 antibodies is correlated with epitope size and proximity to a positively charged IL-16 residue, informing future sweeping antibody development. We demonstrate that anti-IL-16 sweeping antibodies exhibit significantly increased antibody recycling and IL-16 degradation indicating that these molecules are a superior approach for the therapeutic targeting of IL-16 compared to conventional antibodies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/666814v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@108c34corg.highwire.dtl.DTLVardef@4defa1org.highwire.dtl.DTLVardef@af646corg.highwire.dtl.DTLVardef@e9fd2a_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summary: Development of antibodies targeting IL-16 provides insights into sweeping antibody engineering and confers efficient clearance of the cancer- and autoimmunity-associated cytokine interleukin-16.

bioengineering↗

bioRxiv2024

Preventing trogocytosis by cathepsin B inhibition augments CAR T cell function

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which has been suggested to cause CAR T cell fratricide and exhaustion. Whether CMT indeed causes CAR T cell dysfunction and the molecular mechanisms conferring CMT remain unknown. Using a selective degrader of trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen on the CAR T cell surface directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we found that the cysteine protease cathepsin B is essential for CMT and that inhibition of cathepsin B is sufficient to prevent CAR T cell fratricide and exhaustion, leading to improved long-term CAR T cell persistence and anti-tumor activity. Our data demonstrate that it is feasible to separate CMT from cytotoxic activity, that CAR T cell persistence, a key factor associated with clinical CAR T cell efficacy, is directly linked to cathepsin B activity in CAR T cells, and that it is possible to improve CAR T cell function through selective inhibition of CMT. One sentence summary: CAR-mediated trogocytosis is mediated by the cysteine protease cathepsin B and directly causes CAR T cell exhaustion and fratricide. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/598379v3_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@5c058dorg.highwire.dtl.DTLVardef@1707fa7org.highwire.dtl.DTLVardef@ccdff1org.highwire.dtl.DTLVardef@82800b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Restricting CAR T Cell Trafficking Expands Targetable Antigen Space

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin 4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells. One sentence summaryAltering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/579002v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@256b53org.highwire.dtl.DTLVardef@a94775org.highwire.dtl.DTLVardef@1926f62org.highwire.dtl.DTLVardef@cec52e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗