scholarly journals Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity

2017 ◽  
Vol 114 (49) ◽  
pp. E10578-E10585 ◽  
Author(s):  
Nan Guo Ring ◽  
Dietmar Herndler-Brandstetter ◽  
Kipp Weiskopf ◽  
Liang Shan ◽  
Jens-Peter Volkmer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Regulatory Protein ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Antibody Treatment ◽  
Therapeutic Success ◽  
Normal Tissues ◽  
Receptor Signal ◽  
Key Factor ◽  
Antibody Immunotherapy

Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-α (SIRPα) is a myeloid-specific immune checkpoint that engages the “don’t eat me” signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPα with high affinity and disrupts its binding to CD47. Administered by itself, KWAR23 is inert, but given in combination with tumor-opsonizing monoclonal antibodies, KWAR23 greatly augments myeloid cell-dependent killing of a collection of hematopoietic and nonhematopoietic human tumor-derived cell lines. Following KWAR23 antibody treatment in a human SIRPA knockin mouse model, both neutrophils and macrophages infiltrate a human Burkitt’s lymphoma xenograft and inhibit tumor growth, generating complete responses in the majority of treated animals. We further demonstrate that a bispecific anti-CD70/SIRPα antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRPα blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy.

scholarly journals Durable antitumor responses to CD47 blockade require adaptive immune stimulation

2016 ◽  
Vol 113 (19) ◽  
pp. E2646-E2654 ◽  
Author(s):  
Jonathan T. Sockolosky ◽  
Michael Dougan ◽  
Jessica R. Ingram ◽  
Chia Chi M. Ho ◽  
Monique J. Kauke ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Antibody Therapy ◽  
Human Tumor ◽  
Adaptive Immune System ◽  
Immune Checkpoints ◽  
Adaptive Immune ◽  
Receptor Signal ◽  
Programmed Death ◽  
Antitumor Antibodies ◽  
Antitumor Antibody

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

188 Novel Anti-SIRpalpha antibodies with differentiated characteristics as promising cancer therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A202-A202
Author(s):  
Swati Jalgaonkar ◽  
George Huang ◽  
Erin Filbert ◽  
Christine Tan ◽  
Ryan Alvarado ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Regulatory Protein ◽  
Cancer Therapeutics ◽  
Myeloid Cell ◽  
Therapeutic Window ◽  
Close Relative ◽  
Cell Functions ◽  
Tumor Clearance

BackgroundTherapeutically targeting tumor myeloid cells has emerged as a novel and complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor expressed CD47 with SIRP alpha (signal regulatory protein-alphaa, SIRPA) on macrophages, dendritic cells and neutrophils inhibits key immune effector mechanisms. Targeting SIRPa-CD47 represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms.H5F9, an antibody against CD47, has shown promising therapeutic activities in patients with MSD, AML and NHL. However, agents targeting CD47 present hematological toxicities and present a huge antigen sink leading to not achieving an optimum therapeutic window. Our approach is to target SIRP alpha, the receptor of CD47 and focus therapeutic targeting to relevant mechanisms related to phagocytosis and myeloid cell activation and at the same time avoid undesired effects of blocking CD47. SIRP gamma, a very close relative of SIRP alpha is expressed on T cells and also binds to CD47. It has been shown that blockade of SIRP gamma-CD47 interaction inhibits T cell proliferation and blocks trans-endothelial T cell migration. Hence, our aim is to generate SIRP alpha selective antibodies that do not cross-react with SIRP gamma and have minimal impact on T cell functions.MethodsUsing Apexigen’s APXiMAB™ proprietary antibody discovery platform, we have generated two novel anti-SIRP alpha antibodies (APX701 & APX702) with differentiated properties as compared to other approaches targeting the CD47/SIRP alpha axis. We have used ELISA, FACS based cell binding and blocking assays, and functional assays including in vitro phagocytosis and antibody-dependent cell phagocytosis (ADCP) in combination with tumor-opsonizing antibody to select APX701 & APX702.ResultsOur novel preclinical-stage APX701 & APX702 antibodies have demonstrated the following attributes: high binding affinity to human SIRP alpha (APX701 Kd = 0.95nM, APX702 Kd = 0.88nM), no binding to SIRP gamma, efficient blockade of SIRP alpha binding to CD47(APX701 IC50 = 1.04nM, APX702 IC50 = 0.80nM), potent macrophage mediated phagocytosis, enhancement of ADCP mediated by tumor-opsonizing antibody and favorable developability CMC profiles. In comparison with the benchmark antibody OSE-172, APX701 & APX702 showed potent phagocytosis activity and ADCP enhancement in all donors tested while OSE-172 induced phagocytosis in only 50% of the donors. This may result from the fact that APX701 and APX702 bind to all major SIRP alpha variants (V1, V2 & V8; covering ~92% population) while OSE 172 only binds to SIRPalpha V1 (~50% population).ConclusionsAPX701 and APX702 demonstrate differentiated anti-SIRPalpha activities by enhancing myeloid cell-mediated anti-tumor immunity and reactivating critical tumor clearance mechanisms within the tumor microenvironment.

scholarly journals Development of a Fully Human Anti-PDGFRβ Antibody That Suppresses Growth of Human Tumor Xenografts and Enhances Antitumor Activity of an Anti-VEGFR2 Antibody

Neoplasia ◽  
2009 ◽  
Vol 11 (6) ◽  
pp. 594-604 ◽  
Author(s):  
Juqun Shen ◽  
Marie Danielle Vil ◽  
Marie Prewett ◽  
Chris Damoci ◽  
Haifan Zhang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Human Tumor ◽  
Human Tumor Xenografts ◽  
Tumor Xenografts

Diaza- and Triazachrysenes: Potent Topoisomerase-Targeting Agents with Exceptional Antitumor Activity Against the Human Tumor Xenograft, MDA-MB-435

ChemInform ◽  
2003 ◽  
Vol 34 (9) ◽  
Author(s):  
Alexander L. Ruchelman ◽  
Sudhir K. Singh ◽  
Xiaohua Wu ◽  
Abhijit Ray ◽  
Jin-Ming Yang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Human Tumor ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft

scholarly journals Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047589
Author(s):  
Ewelina Dobosz ◽  
Georg Lorenz ◽  
Andrea Ribeiro ◽  
Vivian Würf ◽  
Marta Wadowska ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Immune Responses ◽  
Cell Activation ◽  
Plasma Cells ◽  
Myeloid Cell ◽  
Skin Inflammation ◽  
Adaptive Immune ◽  
Systemic Autoimmunity ◽  
Key Factor ◽  
Old Mice

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

scholarly journals G-CSF: One of The Vehicles for Communication Between Trophoblasts and Macrophages, Which May Cause Problems in Recurrent Spontaneous Abortion

2021 ◽  
Author(s):  
Peng Gao ◽  
Haiyi Liu ◽  
Ying Zha ◽  
Lijie Wei ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Spontaneous Abortion ◽  
Macrophage Activation ◽  
Cell Activity ◽  
Cell Communication ◽  
Recurrent Spontaneous Abortion ◽  
Granulocyte Colony Stimulating Factor ◽  
Pregnancy Failure ◽  
Normal Tissues ◽  
Key Factor ◽  
Stimulating Factor

Abstract Background The etiology of about half of the patients with recurrent spontaneous abortion (RSA) remains unclear, and the imbalance of the immune inflammatory response at the mother-foetal interface may be one of the keys to the onset. Granulocyte-colony stimulating factor (G-CSF) is thought to have a protective effect on pregnancy, and its absence may lead to pregnancy failure, but the evidence is scant. This study aims at investigating whether the loss of G-CSF induced RSA by affecting cell communication at the maternal-foetal interface. Results G-CSF was mainly expressed in villus rather than decidua, and the expression in RSA tissues was lower than that in normal tissues. Down-regulation of G-CSF in trophoblasts resulted in decreased cell activity. Trophoblast-derived exosomes inhibited macrophage activation, while G-CSF free exosomes did not. Intraperitoneal injection of G-CSF improved the pregnancy outcome of RSA mice, and the expression of G-CSF and its receptor at the mother-foetal interface also changed. Conclusion The expression of G-CSF was found to be decreased in villi of patients with RSA. The absence of G-CSF weakens the immune suppression of trophoblasts against macrophages, and the function of trophoblasts is impaired, which may be a key factor in the occurrence of RSA. G-CSF decreased the rate of abortion in RSA mice, and might provide some assistance in the treatment of patients with RSA.

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

1984 ◽  
Vol 2 (4) ◽  
pp. 282-286 ◽  
Author(s):  
S E Salmon ◽  
L Young ◽  
B Soehnlen ◽  
R Liu
Keyword(s):  
Antitumor Activity ◽  
Clonogenic Assay ◽  
Human Tumor ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
Early Results ◽  
Colony Forming Units ◽  
Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

Sign in / Sign up

Export Citation Format

Share Document