GENETICALLY OPTIMIZED IMMUNOTOXINS FOR LEUKEMIA THERAPY
GENETICALLY OPTIMIZED IMMUNOTOXINS FOR LEUKEMIA THERAPY
批准号:
6489315
负责人:
CHRISTOPHER A PENNELL
金额:
$23.1万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-01-30 至 2003-12-31
中文摘要
描述:(申请人摘要)申请人的长期目标是
开发治疗人类T细胞的新型靶向疗法
恶性肿瘤。免疫毒素(ITS)是一类高活性的治疗药物。
特异性程度和独特的作用机制。IT是混合体
由与毒素相连的靶向部分组成的分子。目标定位
部分选择性地与肿瘤细胞结合,并通过
附着的毒素。一般说来,它对人体内的癌细胞有特效。
在人类恶性肿瘤的体外和动物模型中。然而,它是有限的。
临床上由免疫原性、毒性和/或不稳定性决定。A临床级别的IT
明尼苏达大学通过生物化学合成了DA7
脱糖化蓖麻毒素A链(DgRTA)与单抗的连接
针对T细胞相关抗原CD7。DA7的I期临床研究
显示其疗效主要受到不稳定性和非特异性的限制。
血管毒性。尽管有这些限制,DA7还是达到了客观的临床效果
在最大耐受剂量下的反应。如果不稳定和血管
DA7的毒性降低,那么申请人认为DA7可以找到一种
治疗难治性T细胞疾病的利基,或作为一种
手术或放化疗的辅助剂。这一修订的目标是
应用是利用基因工程扩大“治疗窗口”
通过增加DA7的稳定性和降低其毒性。第一
具体目的在于重组ITS的构建和检测
含有与CD7-SPECFICS单链的白喉毒素(DT)衍生物
链Fv(SFV)片段。最初将使用DT,因为它是
唯一一种FDA批准的免疫毒素。SFV结构的修改将是
为了增强稳定性而制造的。用于高水平表达的新方法
可溶性融合毒素,用于IT介导的肿瘤的直接可视化
在体内杀死细胞,都包括在这个目标中。第二个具体目标集中在
通过连接最稳定的SFV来降低毒性(和免疫原性)
结构鉴定在特定的目的L对人类核糖核酸。RNase将是
设计成既能抵抗核糖核酸酶抑制剂,又能最优地
一旦内化就会产生细胞毒性。在特定目标1中提出的所有免疫毒素和
将测试特定目标2的稳定性、相对亲和力
药代动力学、毒性和抗肿瘤活性。这些实验将
允许申请人更准确地确定
稳定性、毒性和有效性。他的最终目标是回到诊所
使用更强大的DA7版本。
英文摘要
DESCRIPTION: (Applicant's Abstract) The applicant's long-term goal is to
develop novel, targeted therapeutics for the treatment of human T cell
malignancies. Immunotoxins (ITs) are a class of therapeutic agents with a high
degree of specificity and a unique mechanism of action. An IT is a hybrid
molecule consisting of a targeting moiety linked to a toxin. The targeting
moiety selectively binds to a tumor cell and targets it for death via the
attached toxin. Generally, ITs are specifically potent against cancer cells in
vitro and in animal models of human malignancies. However, ITs are limited
clinically by immunogenicity, toxicity, and/or instability. A clinical grade IT
called DA7 was synthesized at the University of Minnesota by biochemically
linking deglycosylated ricin toxin A chain (dgRTA) to a monoclonal antibody
specific for the T cell-associated antigen CD7. A Phase I clinical study of DA7
revealed that its efficacy was primarily limited by instability and nonspecific
vascular toxicity. Despite these limitations, DA7 achieved objective clinical
responses at the maximal tolerated dose. If the instability and vascular
toxicity of DA7 were reduced, then the applicant contends that DA7 could find a
therapeutic niche in the treatment of refractory T cell disease, or as an
adjuvant to surgery or chemoradiotherapy. The objective of this revised
application is to use genetic engineering to enlarge the 'therapeutic window'
of DA7 by increasing its stability and decreasing its toxicity. The first
specific aim focuses on the construction and testing of recombinant ITs
containing a derivative of Diphtheria toxin (DT) linked to CD7-specffic single
chain Fv (sFv) fragments. DT will be used initially since it is a component of
the only FDA-approved immunotoxin. Modifications of the sFv structure will be
made to enhance stability. Novel approaches for the high-level expression of
soluble fusion toxins, and for the direct visualization of IT-mediated tumor
cell killing in vivo, are included in this aim. The second specific aim focuses
on decreasing toxicity (and immunogenicity) by linking the most stable sFv
structure identified in Specific Aim l to human RNAses. The RNAses will be
engineered to be both resistant to RNAse inhibitors and to be optimally
cytotoxic once internalized. All immunotoxins proposed in Specific Aim 1 and
Specific Aim 2 will be tested for their stability, relative affinity,
pharmacokinetics, toxicity, and anti-tumor activity. These experiments will
allow the applicant to determine more precisely the relationships between
stability, toxicity, and efficacy. His ultimate goal is to return to the clinic
with a more potent version of DA7.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Unraveling the Pathophysiology of Neurotoxicity Induced by CAR T-cells
-
批准号:10678939
-
项目类别:
-
资助金额:$53.14万
-
财政年份:2022
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Unraveling the Pathophysiology of Neurotoxicity Induced by CAR T-cells
-
批准号:10453491
-
项目类别:
-
资助金额:$54.23万
-
财政年份:2022
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Oxygen as a master immunologic switch
-
批准号:8695091
-
项目类别:
-
资助金额:$30.39万
-
财政年份:2011
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Oxygen as a master immunologic switch
-
批准号:8505412
-
项目类别:
-
资助金额:$29.45万
-
财政年份:2011
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Tracking Immune Activation by Stress Proteins In Vivo
-
批准号:7541420
-
项目类别:
-
资助金额:$25.24万
-
财政年份:2006
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Tracking Immune Activation by Stress Proteins In Vivo
-
批准号:7036312
-
项目类别:
-
资助金额:$25.68万
-
财政年份:2006
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Tracking Immune Activation by Stress Proteins In Vivo
-
批准号:7341718
-
项目类别:
-
资助金额:$25.25万
-
财政年份:2006
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Tracking Immune Activation by Stress Proteins In Vivo
-
批准号:7183492
-
项目类别:
-
资助金额:$25.25万
-
财政年份:2006
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
GENETICALLY OPTIMIZED IMMUNOTOXINS FOR LEUKEMIA THERAPY
-
批准号:6626710
-
项目类别:
-
资助金额:$23.09万
-
财政年份:2001
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
GENETICALLY OPTIMIZED IMMUNOTOXINS FOR LEUKEMIA THERAPY
-
批准号:6263185
-
项目类别:
-
资助金额:$22.68万
-
财政年份:2001
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Cancer Research Career Enhancement and Related Activities
-
批准号:10333233
-
项目类别:
-
资助金额:$5.46万
-
财政年份:1998
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Flow Cytometry Shared Resource
-
批准号:10333241
-
项目类别:
-
资助金额:$14.79万
-
财政年份:1998
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Cancer Research Career Enhancement and Related Activities
-
批准号:10576814
-
项目类别:
-
资助金额:$5.46万
-
财政年份:1998
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
Flow Cytometry Shared Resource
-
批准号:10576829
-
项目类别:
-
资助金额:$14.79万
-
财政年份:1998
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
DESIGN AND USE OF CD7-SPECIFIC RECOMBINANT IMMUNOTOXINS
-
批准号:2100106
-
项目类别:
-
资助金额:$12.54万
-
财政年份:1994
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
DESIGN AND USE OF CD7-SPECIFIC RECOMBINANT IMMUNOTOXINS
-
批准号:2100108
-
项目类别:
-
资助金额:$14.32万
-
财政年份:1994
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
DESIGN AND USE OF CD7-SPECIFIC RECOMBINANT IMMUNOTOXINS
-
批准号:2100107
-
项目类别:
-
资助金额:$13.19万
-
财政年份:1994
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
DESIGN AND USE OF CD7-SPECIFIC RECOMBINANT IMMUNOTOXINS
-
批准号:2008240
-
项目类别:
-
资助金额:$4.94万
-
财政年份:1994
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
DESIGN AND USE OF CD7-SPECIFIC RECOMBINANT IMMUNOTOXINS
-
批准号:2633847
-
项目类别:
-
资助金额:$5.18万
-
财政年份:1994
-
负责人:CHRISTOPHER A PENNELL
-
依托单位:
海外基金