Role of Fc Receptors in the Therapeutic Activity of Antibodies Targeting the CD47-SIRP-alpha axis
Fc 受体在靶向 CD47-SIRP-α 轴的抗体的治疗活性中的作用
基本信息
- 批准号:10689216
- 负责人:
- 金额:$ 15.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdvisory CommitteesAnti-CD47AntibodiesAntitumor ResponseBindingBiological AssayBlocking AntibodiesCD47 geneCD47-SIRPαCD47-SIRPα blockadeCD8-Positive T-LymphocytesCell Surface ReceptorsCellsClassificationClinicClinicalClinical TrialsConsensusCytoprotectionDataDendritic CellsDevelopmentDevelopment PlansEatingEffector CellEngineeringEnsureEnvironmentEpidermal Growth Factor ReceptorFab ImmunoglobulinsFc ReceptorFc(alpha) receptorFlow CytometryFoundationsFundingFutureGoalsGrantHumanImmuneImmune TargetingImmunocompetentImmunocompromised HostImmunoglobulin FragmentsImmunologyImmunotherapyInfiltrationInstitutionInternationalInvestigationLaboratoriesLaboratory ResearchLeadMacrophageMalignant NeoplasmsMediatingMedical OncologyMemorial Sloan-Kettering Cancer CenterMentorsMentorshipMinorityModelingMonoclonal AntibodiesMusMyelogenousMyeloid CellsOutcomePTPNS1 genePathway interactionsPatientsPhagocytesPhagocytosisPhenotypePhysiciansPrognosisQualifyingResearchResearch Project GrantsRoleScientistSignal TransductionSpecimenSystemT cell responseT-Cell ActivationT-Lymphocyte SubsetsTestingTherapeuticToxic effectToxicity TestsTrainingTreatment EfficacyTumor AntigensTumor BiologyTumor ImmunityTumor-associated macrophagesTumor-infiltrating immune cellsUniversitiesVariantanti-PD-1antitumor effectcancer cellcancer immunotherapycancer therapycancer typecareercareer developmentclinical trainingearly phase clinical trialefficacy testingexperiencehuman tissuehumanized mouseimmune cell infiltrateimmune checkpointmouse modelneoplastic cellneutrophilnoveloverexpressionpreclinical studypreventrational designreceptorrecruitresearch studyresponseskillstumortumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Candidate: The PI, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center (MSK), has
developed a 5-year career development plan that builds upon his scientific background in immunology and
clinical training in medical oncology. He will conduct the proposed research under the mentorship of Dr. Jeffrey
Ravetch, an internationally recognized expert in Fc receptors (FcRs). He will also develop new skills in antibody
and tumor biology that are critical for his future career focused on understanding the mechanisms that mediate
effective responses of cancer immunotherapies. The PI has planned to address the necessary training and
mentoring required for his successful transition to independence through select coursework and a robust
mentoring plan. The institutional environment of MSK, The Rockefeller University, and an Advisory Committee
composed of leaders in the field will not only ensure that the PI’s research project progresses as planned, but
also the PI’s transition to independence as a physician-scientist with his own laboratory and grant funding. This
research project is also sufficiently different from his mentor’s to avoid competition or overlap.
Research Plan: Antibodies targeting immune checkpoints lead to long-lasting clinical responses in a variety of
malignancies. However, many patients fail to respond to these therapies and new targets that enhance antitumor
immunity are under active investigation. CD47 is a “don’t eat me” signal overexpressed on several types of
cancer and is associated with poor prognosis. Its expression protects tumor cells from phagocytosis by
interacting with SIRP-alpha (SIRPα), a cell surface receptor expressed on myeloid cells (i.e., macrophages and
dendritic cells). Antibodies blocking the CD47/SIRPα pathway enable myeloid-mediated phagocytosis and tumor
cell elimination, leading to effective antitumor effects in preclinical studies and early clinical trials. The PI studies
have focused on understanding the mechanism of action of antibodies targeting the CD47/SIRPα axis, in
particular the contribution of the antibody Fc domain and its binding to FcRs to induce effective antitumor
responses. Preliminary data presented in this proposal show that a) Engagement of FcRs by the Fc domain
modulates the activity of anti-CD47 and anti-SIRPα antibodies, and b) Fc-optimized anti-CD47 antibodies
increases antitumor immunity and infiltration and of tumor-associated macrophages, dendritic cells, and other
immune cells. The goal of this proposal is to understand the role of specific FcγRs in mediating effective antitumor
responses using a novel humanized mouse model for CD47, SIRPα and FcRs. In this model, Fc-engineered
humanized anti-CD47/SIRPα antibodies will be tested alone or in combination with other immunotherapies to
determine their effects on infiltrating immune cells. Elucidating the role of FcRs as modulators of response to
anti-CD47/SIRPα antibodies may establish a new avenue to maximize their therapeutic actions and provide
critical information on the role of innate immune cells in promoting effective antitumor responses.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Juan C Osorio其他文献
1114-199 A comparison of postnatal changes in fetal phenotype between the left and right ventricles
- DOI:
10.1016/s0735-1097(04)91632-4 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Ana M Duque Gonzalez;Juan C Osorio;Susan Vannucci;Seema Mital - 通讯作者:
Seema Mital
1114-198 Genomic profiles of left ventricular and right ventricular hypertrophy in congenital heart disease
- DOI:
10.1016/s0735-1097(04)91631-2 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Beth D Kaufman;Juan C Osorio;Manisha Desai;Jonathan Chen;Ralph S Mosca;Jan M Quaegebeur;Anthony W Ferrante;Seema Mital - 通讯作者:
Seema Mital
Juan C Osorio的其他文献
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{{ truncateString('Juan C Osorio', 18)}}的其他基金
Role of Fc Receptors in the Therapeutic Activity of Antibodies Targeting the CD47-SIRP-alpha axis
Fc 受体在靶向 CD47-SIRP-α 轴的抗体的治疗活性中的作用
- 批准号:
10526066 - 财政年份:2022
- 资助金额:
$ 15.13万 - 项目类别:
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