Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways
2区 · 医学
作者: Balasa, Balaji ; Yun, Rui ; Belmar, Nicole A. ; Fox, Melvin ; Chao, Debra T. ; Robbins, Michael D. ; Starling, Gary C. ; Rice, Audie G.
Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3(+)CD56(+) lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide.
2013-02-01·Journal of Cancer Research and Clinical Oncology3区 · 医学
Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb
3区 · 医学
作者: Chao, Debra T. ; Su, Mian ; Tanlimco, Sonia ; Sho, Mien ; Choi, Donghee ; Fox, Mel ; Ye, Shiming ; Hsi, Eric D. ; Durkin, Lisa ; Yin, Johnny ; Zhang, Yongke ; Kim, Han ; Starling, Gary C. ; Culp, Patricia A.
The receptor for the cytokine TWEAK (TweakR) is a cell surface member of the tumor necrosis factor receptor superfamily with diverse biological roles. TNFRSF family members are appealing therapeutic targets in oncology due to their aberrant expression and function in tumor cells. The goal of the current study was to examine the potential of TweakR as a therapeutic target in breast cancer.
Expression of TweakR in primary breast cancer tissues and metastases was characterized using immunohistochemistry. To determine the functional relevance of TweakR, breast cancer cell lines were treated in vitro and in vivo with enavatuzumab, a humanized mAb against TweakR.
Overexpression of TweakR was observed in infiltrating tumors compared to normal adjacent breast tissues, and strong staining of TweakR was observed in all subtypes of invasive ductal breast cancer. In addition, a positive correlation of TweakR and HER2 expression and co-localization were observed, irrespective of ER status. TweakR expression was also observed in bone metastasis samples from primary breast cancer but rarely in benign tumors. Enavatuzumab inhibited the in vitro growth of TweakR-expressing breast cancer cell lines, and this activity was augmented by cross-linking the mAb. In addition, enavatuzumab significantly inhibited the in vivo growth of multiple breast cancer xenograft models including a model of metastasis.
TweakR is highly expressed in all subtypes of invasive ductal breast cancer, and enavatuzumab administration exhibited a dose-dependent inhibition of primary tumor growth and lung metastasis and enhanced the antitumor activity of several chemotherapy agents currently used to treat breast cancer. These data provide the rationale to evaluate enavatuzumab as a potential therapy for the treatment of breast cancer.
2012-11-01·Journal of Immunology2区 · 医学
Affinity and Cross-Reactivity Engineering of CTLA4-Ig To Modulate T Cell Costimulation
2区 · 医学
作者: Xu, Zhenghai ; Juan, Veronica ; Ivanov, Alexander ; Ma, Zhiyuan ; Polakoff, Dixie ; Powers, David B. ; DuBridge, Robert B. ; Wilson, Keith ; Akamatsu, Yoshiko
CTLA4-Ig is an Fc fusion protein containing the extracellular domain of CTLA-4, a receptor known to deliver a negative signal to T cells. CTLA4-Ig modulates T cell costimulatory signals by blocking the CD80 and CD86 ligands from binding to CD28, which delivers a positive T cell costimulatory signal. To engineer CTLA4-Ig variants with altered binding affinity to CD80 and CD86, we employed a high-throughput protein engineering method to map the ligand binding surface of CTLA-4. The resulting mutagenesis map identified positions critical for the recognition of each ligand on the three CDR-like loops of CTLA-4, consistent with the published site-directed mutagenesis and x-ray crystal structures of the CTLA-4/CD80 and CTLA-4/CD86 complexes. A number of single amino acid substitutions were identified that equally affected the binding affinity of CTLA4-Ig for both ligands as well as those that differentially affected binding. All of the high-affinity variants showed improved off-rates, with the best one being a 17.5-fold improved off-rate over parental CTLA4-Ig binding to CD86. Allostimulation of human CD4(+) T cells showed that improvement of CD80 and CD86 binding activity augmented inhibition of naive and primed T cell activation. In general, increased affinity for CD86 resulted in more potent inhibition of T cell response than did increased affinity for CD80. Optimization of the affinity balance to CD80 and CD86 to particular disease settings may lead to development of a CTLA4-Ig molecule with improved efficacy and safety profiles.
- Accomplished life sciences executive brings nearly four decades of experience in pharmaceutical and biotechnology drug development and business operations -
ANN ARBOR, Mich., June 27, 2022 /PRNewswire/ -- Sling Therapeutics, Inc., a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED), today announced the appointment of Faheem Hasnain as chairman of the company's Board of Directors.
"We are pleased to welcome Faheem to our Board and look forward to benefiting from his extensive experience successfully bringing novel treatments to patients around the world," said Ryan Zeidan, Ph.D., President and Chief Executive Officer of Sling Therapeutics. "TED is a debilitating autoimmune disease and there are significant barriers to access current treatment options. We have a clear opportunity to rapidly advance the evaluation of linsitinib, which will be the first oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor to enter late-stage clinical trials for TED."
Mr. Hasnain is the founder, chief executive officer, and chairman of Gossamer Bio. He also serves as the lead independent director for Kura Oncology and is chairman of the Board of Directors for Aspen Neuroscience, Mirati Therapeutics and SENTÉ. Mr. Hasnain is the former president and chief executive officer of Receptos, Facet Biotech and PDL BioPharma. He holds a B.H.K and a B.Ed. from the University of Windsor.
"Sling Therapeutics has built a team that has extensive drug development and operations experience," said Mr. Hasnain. "With the engagement of a scientific advisory board comprised of global experts in TED, Sling is tackling a debilitating autoimmune disease that affects about 20,000 people in the U.S annually. The company is developing a convenient oral therapy for TED, and I look forward to supporting the company through the launch of the late-stage clinical program."
About Sling Therapeutics
Sling Therapeutics, Inc., is a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED). The company is advancing the evaluation of its lead product candidate, linsitinib, in a Phase 2b clinical trial based on extensive preclinical and clinical data. Linsitinib offers the potential of a convenient oral small molecule that could significantly reduce the treatment burden for people living with TED. For more information visit .
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