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。可以逆转MDR和化疗增敏的药剂在有效剂量下通常是有毒的。因此，期望开发仅作用于肿瘤细胞的无毒化学增敏剂。我们先前已经证明，在MDR+ B细胞淋巴瘤中，单克隆抗CD 19抗体可以通过干扰P-糖蛋白（Pgp）从细胞中排出药物的能力来逆转Pgp介导的MDR。我们现在提出，以确定如何抗CD 19逆转MDR和抗CD 19是否可以化疗增敏MDR+淋巴瘤细胞在体内。如果是这样的话，我们将尝试通过将抗CD 19与化疗和靶向免疫毒素（IT）结合来治疗患有晚期MDR+淋巴瘤的SCID小鼠，从而进一步降低化疗。本竞争性更新提案的具体目标是：1。继续阐明抗CD 19在体外降低Pgp介导的MDR的机制。我们将测试两个假设：i）Pgp的功能受损，因为在CD 19交联并进入脂筏后，Pgp被迫离开质膜的低密度脂质微区（“脂筏”）（其中它是活性的），和ii）抗CD 19通过调节细胞内pH（pHi）并因此干扰细胞中的药物积累而损害Pgp的功能。2.确定这些单克隆抗体是否可以减少Pgp介导的MDR在体内的SCID/淋巴瘤小鼠化疗前或化疗期间。3.确定MDR逆转MAb和MDR旁路抗CD 22 IT联合给药时可给予的最低化疗剂量。总之，这些信息应该帮助我们确定如何优化人类MDR+淋巴瘤的单克隆抗体治疗，以及开发新的方法来使用单克隆抗体与其他常规和实验性抗肿瘤药物。

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.