The reversal of multidrug resistance by an anti-CD19 ab.

描述（由申请人提供）：多药耐药（MDR）是复发性淋巴瘤的主要问题。能逆转耐多药和化学增敏的药物在有效剂量下往往是有毒的。因此，开发仅作用于肿瘤细胞的无毒化学增敏剂是可取的。我们之前已经证明单克隆抗cd19抗体可以通过干扰p糖蛋白（Pgp）从细胞外排药物的能力，在体外逆转MDR+ B细胞淋巴瘤中p糖蛋白介导的MDR。我们现在提议确定抗cd19如何逆转MDR，以及抗cd19是否可以在体内使MDR+淋巴瘤细胞化疗敏感。如果是这样，我们将尝试进一步降低化疗，通过将抗cd19与化疗和靶向免疫毒素（IT）联合治疗晚期MDR+淋巴瘤的SCID小鼠。这一竞争性更新提案的具体目标是：1。继续阐明抗cd19在体外减少pgp介导的多药耐药能力的机制。我们将测试两个假设：1)Pgp的功能受损，因为在CD19交联并进入质膜的低密度脂质微域（“脂质筏”）后，Pgp被迫离开质膜（它活跃的地方）；ii)抗CD19通过调节细胞内ph值（pHi）从而干扰细胞内药物积累而损害Pgp的功能。2. 确定在化疗前或化疗期间给药这些单克隆抗体是否能降低pgp介导的SCID/淋巴瘤小鼠体内耐多药。3. 确定当逆转耐多药单克隆抗体和绕过耐多药的抗cd22 IT同时使用时可给予的最低化疗剂量。综上所述，这些信息应该有助于我们确定如何优化人类MDR+淋巴瘤的单克隆抗体治疗，以及开发新的方法，将单克隆抗体与其他传统和实验性抗肿瘤药物结合使用。

DESCRIPTION (provided by applicant): Multidrug resistance (MDR) is a major problem in relapsed lymphomas. Agents which can reverse MDR and chemosensitize are often toxic at effective doses. It would therefore be desirable to develop non-toxic chemosensitizers which act only on tumor cells. We have previously shown that a monoclonal anti-CD19 antibody can reverse P-glycoprotein (Pgp)-mediated MDR in an MDR+ B cell lymphoma in vitro by interfering with the ability of Pgp to efflux drugs from the cells. We now propose to determine how anti-CD19 reverses MDR and whether anti-CD19 can chemosensitize MDR+ lymphoma cells in vivo. If so, we will attempt to lower chemotherapy even further by combining the anti-CD19 with chemotherapy and a targeted immunotoxins (IT) to treat SCID mice with advanced MDR+ lymphoma. The Specific Aims of this competitive renewal proposal are: 1. To continue to elucidate the mechanisms underlying the ability of anti-CD19 to decrease Pgp-mediated MDR in vitro. We will test two hypotheses: i) The function of Pgp is impaired because it is forced out of the low-density lipid microdomains ("lipid rafts") of the plasma membrane (where it is active) after CD19 is crosslinked and enters rafts, and ii) anti-CD19 impairs the function of Pgp by modulating of intracellular ph (pHi) and hence interfering with drug accumulation in cells. 2. To determine whether these MAbs can decrease Pgp-mediated MDR in vivo in SCID/lymphoma mice when administered before or during chemotherapy. 3. To determine the lowest doses of chemotherapy which can be given when both the MDR-reversing MAbs and the MDR-bypassing anti-CD22 IT are co-administered. Taken together, this information should help us determine how to optimize the MAb therapy of MDR+ lymphoma in humans as well as to develop novel ways to use MAbs in conjunction with other conventional and experimental anti-tumor agents.