Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
批准号:
10403976
负责人:
Roland Bruno Walter
金额:
$20.16万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-07-01 至 2024-06-30
关键词:
Acute Myelocytic LeukemiaAntibodiesAntibody TherapyAntibody-drug conjugatesBindingBispecific AntibodiesBlocking AntibodiesCD28 geneCD3 AntigensCD69 antigenCell LineCell physiologyCell surfaceCell-Mediated CytolysisCellsDevelopmentDiseaseDistalDrug TargetingEngineeringEpitopesFCGR3B geneGemtuzumab OzogamicinGlycoproteinsHumanImmuneImmunotherapyIn VitroIndividualLengthLigandsLocationMalignant lymphoid neoplasmMembraneModalityNK cell therapyNatural Killer CellsOutcomePD-1/PD-L1PatientsPhasePlayPositioning AttributeProteinsReceptor CellReceptor SignalingResearchResistanceRoleSET DomainSeriesSignal TransductionSpecificityT-Cell ActivationT-LymphocyteTestingTherapeuticToxic effectVariantWorkacute leukemia cellacute myeloid leukemia cellbasecancer therapychimeric antigen receptor T cellscrosslinkcytokine release syndromeefficacy testingexpectationhumanized mouseimprovedimproved outcomein vivoinsightinterestleukemialeukemic stem cellmouse modelnovelnovel therapeuticspreclinical studyprogrammed cell death ligand 1receptorresearch clinical testingsuccesstargeted treatmenttooltumor
中文摘要
摘要
CD 33靶向治疗长期以来一直在急性髓性白血病(AML)中进行。一些人的生存时间更长
用抗体-药物缀合物吉妥珠单抗(gemtuzumab ozogamicin,GO)治疗的患者验证了这种方法,但是
许多CD 33 + AML患者不能从GO中获益。这促使人们努力开发更好的CD 33-
定向治疗剂,包括T细胞接合双特异性抗体(BsAb)。最近,几名特工
进入早期临床试验,初步结果表明,一些疗效,但也有大量的毒性,
与T细胞活化相关的精氨酸释放综合征因此,人们越来越关注探索
其他免疫细胞如自然杀伤(NK)细胞的效用(例如通过CD 16的接合),其可能
规避这些限制。如何优化CD 33/CD 16导向疗法尚不清楚。作为一个限制,
在CD 33靶向治疗中,CD 33抗体(包括GO)通常识别免疫显性表位
位于膜远端V形组区域内。在我们用CD 33 V-set/CD 3 BsAb和人工
然而,我们已经观察到,随着膜近端CD 33蛋白表达的增加,T细胞介导的细胞毒性增强。
CD 33的结合。因此,我们已经产生了一系列针对膜近端C2-set的抗体,
识别所有天然存在的CD 33变体(即“CD 33 PAN抗体”)的CD 33结构域作为基础
用于新的治疗方法。我们以前的研究也表明,T细胞定向的BsAb的抗肿瘤功效
通过抑制性T细胞共受体信号传导,例如通过PD-L1/PD-1轴消除。我们进一步表明
使用成对的BsAb结合并阻断这种抑制信号,同时反过来提供共刺激,
对T细胞的刺激(例如通过交联CD 28)可以将细胞抑制转化为活化,并且显著地
增加T细胞接合BsAb的功效。到目前为止,激活和抑制NK受体及其
还没有评估相应的配体作为基于BsAb的NK细胞疗法的调节剂。基于我们
在使用T细胞接合BsAb的研究中,我们假设CD 33/CD 16导向的NK细胞接合疗法可以是
通过CD 33的膜近端靶向进行优化。我们还预测,激活和抑制NK细胞配体
调节CD 33/CD 16 BsAb的抗肿瘤功效,因此,
BsAb可以通过与结合/阻断抑制性NK细胞配体并刺激NK细胞增殖的BsAb配对来逆转。
激活NK细胞受体。我们将在体外和体内的良好对照的临床前研究中测试这些假设。
在完成拟议的研究后,我们期望我们已经获得了关键的洞察力,
可以最大化CD 33/CD 16 NK细胞接合治疗剂的抗AML功效。我们的工作预计将
具有重要的积极影响,因为它可以形成优化NK细胞接合治疗剂的基础,
AML和其他CD 33+疾病患者,其结局仍然不令人满意。
英文摘要
ABSTRACT
CD33-targeted therapies have long been pursued in acute myeloid leukemia (AML). Longer survival of some
patients treated with the antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this approach, but
many patients with CD33+ AML do not benefit from GO. This has prompted efforts to develop better CD33-
directed therapeutics, including T cell engaging bispecific antibodies (BsAbs). Several agents have recently
entered early phase clinical testing, with initial results indicating some efficacy but also substantial toxicities from
cytokine-release syndrome associated with T cell activation. There is therefore increasing focus on exploring the
utility of other immune cells such as natural killer (NK) cells (e.g. via engagement of CD16), which might
circumvent these limitations. How CD33/CD16-directed therapy can be optimized is unknown. As one limitation
of CD33-targeted therapy, CD33 antibodies (including GO) typically recognize immune-dominant epitope(s)
within the membrane-distal V-set domain. In our preliminary studies with CD33V-set/CD3 BsAbs and artificial
CD33 proteins, however, we have observed enhanced T cell-mediated cytotoxicity with membrane-proximal
binding of CD33. We have therefore generated a series of antibodies against the membrane-proximal C2-set
domain of CD33 that recognize all naturally occurring variants of CD33 (i.e. are “CD33PAN antibodies”) as basis
for novel therapeutics. Our previous studies have also shown that the anti-tumor efficacy of T cell-directed BsAbs
is abrogated by inhibitory T cell co-receptor signaling, e.g. via the PD-L1/PD-1 axis. We further demonstrated
that the use of a paired BsAb which binds and blocks such an inhibitory signal while, in turn, providing co-
stimulation to T cells (e.g. via cross-linking CD28) can convert cellular inhibition into activation and dramatically
increase the efficacy of T cell engaging BsAbs. So far, the role of activating and inhibitory NK receptors and their
corresponding ligands as modulators of BsAb-based NK cell therapy has not been evaluated. Based on our
studies with T cell-engaging BsAbs, we hypothesize CD33/CD16-directed NK cell engaging therapy can be
optimized by membrane-proximal targeting of CD33. We also predict that activating and inhibitory NK cell ligands
modulate the anti-tumor efficacy of CD33/CD16 BsAbs and that, consequently, the resistance to CD33/CD16
BsAbs can be reversed by pairing with a BsAb that binds/blocks an inhibitory NK cell ligand and stimulates an
activating NK cell receptor. We will test these hypotheses in well-controlled preclinical studies in vitro and in vivo.
Upon completion of the proposed research, it is our expectation that we have gained critical insight into how the
anti-AML efficacy of CD33/CD16 NK cell-engaging therapeutics can be maximized. Our work is anticipated to
have an important positive impact because it may form the basis for optimized NK cell engaging therapeutics for
patients with AML and other CD33+ disorders, for which outcomes continue to be unsatisfactory.
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会议论文
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CAR T-Cell Therapy Targeting the Membrane-Proximal C2-Set Domain of CD33 for Treatment of Acute Myeloid Leukemia and Other CD33-Expressing Hematopoietic Neoplasms
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Prognostic and Functional Significance of Adhesion Molecules in Pediatric AML
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海外基金