Clinical Translation of an Anti-Metastatic Antibody for Breast Cancer Therapy

抗转移抗体用于乳腺癌治疗的临床转化

• 批准号: 9041550
• 负责人: Kate W Rittenhouse-Olson
• 金额: $ 101.36万
• 依托单位: FOR-ROBIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041550
• 关键词: Address; Antibodies; Antibody-drug conjugates; Binding; Biological; Bladder; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Cancer therapy; Cancer Patient; Carcinoma; Cell-Mediated Cytolysis; Chemicals; Clinical; Colon; Data; Development; Diagnostic; Drug Kinetics; Evaluation; Exhibits; Future; Generations; Health; Human; IgG1; Immunohistochemistry; Immunotherapeutic agent; Investigational New Drug Application; Lead; Legal patent; Malignant Neoplasms; Mammary Neoplasms; Marketing; Metastatic breast cancer; Modeling; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Patients; Phase; Property; Prostate; Radiolabeled; Research; Robin bird; Safety; Small Business Technology Transfer Research; Specificity; Surface; Testing; Therapeutic; Tissues; Toxicology; Translations; Xenograft Model; Xenograft procedure; base; conventional therapy; drug candidate; effective therapy; improved outcome; killings; malignant breast neoplasm; microPET; neoplastic cell; novel; oncology; phase 3 study; pre-clinical; radiotracer; success; translational study; triple-negative invasive breast carcinoma; tumor; tumor growth

 DESCRIPTION (provided by applicant): Translational studies are proposed to support the continued development of the JAA-F11 antibody based therapy to address the critical need for a safe and effective treatment for metastatic breast cancer, including triple negative breast cancers. Building on the success of our Phase I project, the overarching objectives of the Phase II application are to advance translational studies with humanized JAA-F11 (hJAA- F11). These novel IgG1 antibodies binds with high specificity to the pancarcinoma Thomsen-Friedenreich glycoantigen (TF-Ag; Galß1-3GalNAc alpha), which is a unique target expressed on the surface of about 80% of breast, colon, bladder, prostate and other carcinomas, but not on normal tissues. The successful generation of 3 humanized and one chimeric JAA-F11 constructs, which have the same unique chemical specificity for TF- Ag as our patented mouse monoclonal antibody mJAA-F11 directly supports the hypothesis of our Phase I application, that humanization of JAA-F11 can yield an antibody of the same chemical and biologic specificity as the original mJAA-F11. In addition, there is active progress on generation of up to an additional 6 humanized constructs that will be evaluated to identify lead antibody candidates. The hypothesis of the Phase II application is that humanized constructs (hJAA-F11) can be used therapeutically to create a survival advantage for patients with breast cancers, including triple negative breast cancers, through direct killing and by blocking tumor cell spread. Specific aims of this application are focused on identifying lead drug candidates and generating preclinical data in support of an Investigational New Drug (IND) application for therapeutic and diagnostic applications of hJAA-F11 in breast cancer patients. Aim 1 will identify 2 lead antibody candidates (hJAA-F11 constructs), one of which supports the use of the antibody as a direct cancer immunotherapeutic agent and the second which supports the use as an antibody-drug conjugate. Both candidates will demonstrate high chemical and biological specificity for TF-Ag positive tumors. The lead immunotherapeutic candidate will have high antibody directed cellular cytotoxicity (ADCC) activity and the lead candidate for an antibody drug conjugate will have rapid tumor cell internalization. Aim 2 will assess the efficacy of hJAA-F11 constructs on tumor growth rate in a xenograft human breast cancer model in Nude mice. Efficacy studies will be conducted with the construct having optimal ADCC activity and the construct with optimal internalization will be tested as an antibody-linker-maytansine derivative. Aim 3 will conduct pharmacokinetic studies of these hJAA-F11 constructs in mice with and without tumors. Evaluation of the pharmacokinetics of hJAA-F11 constructs is critically important to the

 描述（由应用提供）：提出了转化研究，以支持基于JAA-F11抗体的持续发展，以解决对转移性乳腺癌（包括三重阴性乳腺癌）安全有效治疗的关键需求。在我们阶段项目的成功的基础上，第二阶段应用程序的总体对象是通过人源化JAA-F11（HJAA-F11）进行转化研究。这些新型的IgG1抗体具有高特异性与Thomsen-friedenreich糖素（TF-AG;Galß1-3GalnacAlpha）的特异性，该抗体是在约80％的胸部，结肠，膀胱，前列腺和其他人的乳房，结肠，膀胱和其他正常组织的表面上表达的独特靶标，但在约80％的表面上表达。成功产生的3个人源化和1个嵌合JAA-F11结构，它们的TF-AG具有与我们专利的小鼠单克隆抗体MJAA-F11相同的独特化学特异性，直接支持了我们阶段应用的假设，与JAA-F11的人性化可以产生与原始MJAA-F11相同化学和生物学特异性的抗体。此外，在产生多达6种人源化构建体方面，还将进行评估以识别铅抗体候选物。 II期应用的假设是，可以在治疗上使用人性化构建体（HJAA-F11）来通过直接杀死和阻断肿瘤细胞扩散来为乳腺癌（包括三重阴性乳腺癌）患者创造生存优势。该应用的具体目的集中在识别铅药物候选者并生成临床前数据，以支持HJAA-F11在乳腺癌患者中的治疗和诊断应用中的研究新药（IND）应用。 AIM 1将识别2种铅抗体候选（HJAA-F11构建体），其中一种支持将抗体用作直接癌症免疫治疗剂，第二种支持用作抗体 - 毒剂偶联物。两种候选者将表现出对TF-AG阳性肿瘤的高化学和生物学特异性。铅免疫治疗候选者将具有高抗体定向的细胞毒性（ADCC）活性，并且抗体药物结合物的主要候选者将具有快速的肿瘤细胞内在化。 AIM 2将评估裸鼠异种移植人类乳腺癌模型中HJAA-F11构建体的效率。功效研究将使用具有最佳ADCC活性的构建体进行，并且具有最佳内在化的构建体将作为一种抗体链链 - 融合衍生物进行测试。 AIM 3将对具有和没有肿瘤的小鼠中这些HJAA-F11构建体进行药代动力学研究。评估HJAA-F11构建体的药代动力学对

项目成果

Corrigendum to "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" [Neoplasia 19.9 (2017) 716-733].

“高度特异性抗 Thomsen-Friedenreich 胰腺癌抗体 JAA-F11 的人源化和体外功效分析”的勘误表 [Neoplasia 19.9 (2017) 716-733]。

• DOI: 10.1016/j.neo.2017.10.001
• 发表时间: 2018
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Tati,Swetha;Fisk,JohnC;Abdullah,Julia;Karacosta,Loukia;Chrisikos,Taylor;Philbin,Padraic;Morey,Susan;Ghazal,Diala;Zalzala,Fatma;Jessee,Joseph;Quataert,Sally;Koury,Stephen;Moreno,David;Eng,JingYing;Glinsky,VladislavV;Glinski
• 通讯作者: Glinski

Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

• DOI: 10.1016/j.tranon.2018.01.008
• 发表时间: 2018-04
• 期刊: Translational oncology
• 影响因子: 5
• 作者: Karacosta LG;Fisk JC;Jessee J;Tati S;Turner B;Ghazal D;Ludwig R;Johnson H;Adams J;Sajjad M;Koury S;Roy R;Olson JR;Rittenhouse-Olson K
• 通讯作者: Rittenhouse-Olson K

Therapeutic efficacy of the humanized JAA-F11 anti-Thomsen-Friedenreich antibody constructs H2aL2a and H3L3 in human breast and lung cancer xenograft models.

• DOI: 10.18632/oncotarget.28282
• 发表时间: 2022-10-19
• 期刊: Oncotarget