Author: Liu, Sheng ; Wang, Quan ; Jin, Hong Ri ; Jung, Sung Han ; Lo, Ho-Yin ; Bellail, Anita C ; Kim, Daeho ; Hao, Chunhai ; Zhao, Yin Quan ; Fu, Xue Qi ; Wan, Jun

Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screen has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader's anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).

01 Nov 2022·Transfusion

Anti‐CD38 monoclonal antibody interference with blood compatibility testing: Differentiating isatuximab and daratumumab via functional epitope mapping

Article

Author: Fukao, Taro ; Hidaka, Yoko ; Okuda, Makoto ; Song, Zhili ; Zhang, Bailin ; Pirenne, France ; Nambiar, Ashok ; Bedel, Olivier ; Hopke, Joern ; Chami, Btissam ; Moayeri, Morvarid ; Chiron, Marielle ; Martin, Thomas ; Basile, Frank G. ; Deng, Gejing ; Macé, Sandrine ; Zhu, Chen ; Adrian, Francisco

AbstractBackgroundThere are two FDA‐approved anti‐CD38 monoclonal antibodies for treatment of multiple myeloma: isatuximab and daratumumab. Owing to expression of CD38 on reagent red blood cells (RBCs), these antibodies interfere with indirect antiglobulin tests (IATs). We sought to understand differences in such interference by performing binding experiments.Study Design and MethodsIn vitro experiments to compare the binding to RBCs of isatuximab and daratumumab alone or in the presence of a mouse anti‐human CD38 antibody (HB‐7 or AT13/5) or a nicotinamide adenine dinucleotide‐analog CD38 inhibitor were performed and quantified by flow cytometry, imaging, mass spectrometry, surface plasmon resonance, and LigandTracer technologies. Serologic testing was performed on plasma samples spiked with isatuximab or daratumumab.ResultsCD38 expressed on RBCs can be directly bound by daratumumab, whereas isatuximab requires a co‐factor, such as HB‐7, AT13/5, or a CD38 inhibitor, suggesting that the isatuximab epitope on RBCs is masked in vitro. Daratumumab samples more frequently showed interference and had stronger reactions than isatuximab samples. Dithiothreitol treatment was equally effective in mitigating the interference caused by either drug.DiscussionBoth isatuximab and daratumumab interfere with IATs but at different magnitudes, reflecting distinct binding to CD38 on RBCs. From the binding studies, we conclude that the isatuximab epitope on RBCs is masked in vitro and binding requires a certain CD38 conformation or co‐factor. This circumstance may explain why interference is seen only in a subset of patients receiving isatuximab when compared with interference seen in most patients on daratumumab therapy.

01 Dec 1997·Journal of immunology (Baltimore, Md. : 1950)

Protein-tyrosine phosphorylation by IgG1 subclass CD38 monoclonal antibodies is mediated through stimulation of the FcgammaII receptors in human myeloid cell lines.

Article

Author: Tsujimoto, N ; Hazeki, O ; Katada, T ; Kanda, Y ; Inoue, S ; Kontani, K ; Hosoda, N ; Hoshino, S

The human surface Ag CD38 is a 46-kDa type II transmembrane glycoprotein, and its expression is dependent on the cell differentiation and activation of lymphocytes. Our previous work in human myeloid cells showed that ligation of CD38 with mAbs (HB-7 and T-16; IgG1 subclass) not only induced protein-tyrosine phosphorylation but also potentiated superoxide generation stimulated by G protein-coupled receptors. In the present study we analyzed the mechanisms of action of the agonistic mAbs. HB-7-induced tyrosine phosphorylation could be still observed in human myeloid cells expressing CD38 mutants, of which cytoplasmic and transmembrane domains had been deleted or replaced by those of another type II glycoprotein (PC-1). Moreover, N-linked glycosylation on the cell surface CD38 was not required for the HB-7-induced cell signaling. The profile of tyrosine-phosphorylated proteins by HB-7 was exactly the same as that induced by cross-linking of FcgammaII receptors (FcgammaRII/CD32), and FcgammaRII itself was tyrosine phosphorylated in the two stimulated cells. The HB-7-induced tyrosine phosphorylation was completely abolished after masking of FcgammaRII with its mAb. Finally, F(ab')2 of HB-7 failed to mimic the actions of the whole form of mAb. These results indicate that anti-CD38 mAb-induced tyrosine phosphorylation and its associated cell response are entirely mediated through the FcgammaRII-induced signaling pathway, possibly resulting from stimulation of the cell surface human FcgammaRII with the mouse Fc region (IgG1 subclass) of CD38-ligated mAbs.

100 Deals associated with HB-007

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Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Neoplasms	Preclinical	US	HB Therapeutics, Inc.	13 Oct 2021
Central Nervous System Neoplasms	Preclinical	US	Synovel Laboratory LLCStartup	13 Oct 2021
Central Nervous System Neoplasms	Preclinical	US	Indiana University	13 Oct 2021
Central Nervous System Neoplasms	Preclinical	GB	Horizon Discovery Ltd.	13 Oct 2021

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