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

描述（由申请人提供）：多药耐药性（MDR）是复发性淋巴瘤的一个主要问题。能够逆转多药耐药和化疗增敏的药物在有效剂量下通常是有毒的。因此，需要开发仅作用于肿瘤细胞的无毒化学增敏剂。我们之前已经证明，单克隆抗 CD19 抗体可以通过干扰 Pgp 从细胞中流出药物的能力，在体外逆转 MDR B 细胞淋巴瘤中 P-糖蛋白 (Pgp) 介导的 MDR。我们现在建议确定抗CD19如何逆转MDR以及抗CD19是否可以在体内使MDR淋巴瘤细胞化疗增敏。如果是这样，我们将尝试通过将抗 CD19 与化疗和靶向免疫毒素 (IT) 相结合来进一步降低化疗水平，以治疗患有晚期 MDR 淋巴瘤的 SCID 小鼠。该竞争性更新提案的具体目标是： 1. 继续阐明抗 CD19 体外降低 Pgp 介导的 MDR 能力的机制。我们将测试两个假设：i) Pgp 的功能受到损害，因为在 CD19 交联并进入筏后，Pgp 被迫离开质膜（其活跃的地方）的低密度脂质微结构域（“脂筏”）；ii) 抗 CD19 通过调节细胞内 ph (pHi) 损害 Pgp 的功能，从而干扰细胞内的药物积累。 2. 确定这些 MAb 在化疗前或化疗期间施用时是否可以降低 SCID/淋巴瘤小鼠体内 Pgp 介导的 MDR。 3.确定当MDR逆转MAb和MDR绕过抗CD22 IT同时施用时可以给予的最低化疗剂量。总而言之，这些信息应有助于我们确定如何优化人类 MDR 淋巴瘤的 MAb 疗法，以及开发将 MAb 与其他常规和实验性抗肿瘤药物结合使用的新方法。

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.