Doxorubicin-Immunoconjugate Therapy of Non-Hodgkin's Lymphoma

单抗与药物或毒素的偶联已被研究多年，作为一种 将这些药物更具体地输送到癌症的潜在方法。一种这样的化合物，Mylotarg？，a 抗CD33抗体与高效细胞毒药物Calicheamicin的结合已获得FDA批准 用于治疗60岁以上首次复发的CD33阳性急性髓系白血病患者。其他药物-MAb 结合物目前正在开发中，用于治疗各种实体肿瘤。尽管有些人建议 传统抗癌药物的单抗结合物，如阿霉素(Dox)将不具有足够的效力 为了获得显著的治疗效果，我们积累了大量证据表明，正确的 抗原-抗体靶向系统可以产生高效的Dox-免疫结合物。 CD74是一种与人类白细胞抗原DR相关的11型跨膜伴侣分子，可抑制抗原结合 多肽向第II类抗原递呈结构。它在几种类型的肿瘤细胞表面表达 (例如，NHL、MM、黑色素瘤和肾细胞癌细胞)，并引导从表面到内体隔室的运输 在细胞内。我们已经展示了放射性核素抗体结合物对CD74+B细胞的强大活性，使用 俄歇电子发射体标记靶CD74的快速内化LL1抗体。这些结果提供了 测试LL1-抗CD74单抗用于药物传递的动力。阿霉素，治疗NH的关键药物，L 它为药物结合疗法提供了许多优点，包括：(A)水溶性，因此很容易 与蛋白质水溶液相容；(B)具有几个化学反应基团；(C)具有几个 作用机制，包括抑制拓扑异构酶II、插入DNA和破坏细胞 膜。LL1-Dox在系统性非霍奇金淋巴瘤异种移植模型中的治疗效果显著(见 初步结果和附稿)。 非霍奇金淋巴瘤(NHL)是美国第五大常见癌症，占所有癌症的5%。 每年相关死亡人数。5年治愈率只有50%。众所周知，这些肿瘤表达大量的 CD74抗原。NHL可能对使用药物-AB结合物的特定靶向方法反应最好，因为它 广泛传播的性质和癌细胞对全身给药药物的相对可及性。在……里面 另外，血液系统肿瘤的内在敏感性越大，这种疾病的自然病程与细胞 生长失控，最终数量超过正常的B细胞，提供了更高的机会 。与正常细胞相比，注射的药物-抗体对患病细胞的比率。因此，这项提议将 阐述LL1-Dox免疫结合物治疗播散性非霍奇金淋巴瘤的效用 临床前模型和原发NHL活检标本。我们还将讨论几个新的生物学问题 包括(A)克服多药耐药的可能性(通常表现为~60%的难治性非霍奇金淋巴瘤 患者)通过直接将Dox与抗体一起递送，以及(B)克服与 免费给药阿霉素。

Conjugates of monoclonal antibodies (MAbs) with drugs or toxins have been investigated for many years as a potential approach to delivering these agents more specifically to cancers. One such compound, Mylotarg¿, a conjugate of the anti-CD33 antibody with the highly potent cytotoxic drug, calicheamicin, has gained FDA approval for treatment of CD33-positive acute myeloid leukemia in patients over age 60 in first relapse. Other drug-MAb conjugates are currently in development for the treatment of various solid tumors. Although some have suggested that Mab conjugates of conventional anticancer drugs, such as doxorubicin (Dox) would not have adequate potency to elicit a significant therapeutic effect, we have accumulated a large body of evidence showing that the correct antigen-antibody targeting system can result in a highly effective Dox-immunoconjugate. CD74 is a type-ll transmembrane chaperone molecule that associates with HLA-DR, inhibiting binding of antigenic peptides to the class-ll antigen presentation structure. It is expressed on the surface of several types of tumor cells (e.g., NHL, MM, melanoma and RCC cells) and directs transport from the surface to an endosomal compartment within the cell. We have shown potent activity of antibody conjugates of radionuclides against CD74+ B cells, using the rapidly internalizing LL1 antibody to target CD74 labeled with Auger electron emitters. These results provided the impetus to test the LL1-anti-CD74 Mab for drug delivery. Doxorubicin, a key drug in the management of NH,L affords many advantages for drug-conjugate therapy including: (a) water-soluble nature and therefore readily compatible with aqueous protein solutions; (b) having several chemically reactive groups; (c) possessing several mechanisms of action, including inhibition of topoisomerase II, intercalation into DNA, and disrupting on cell membranes. Therapeutic results with LL1-Dox in a systemic NHL xenograft model have been outstanding (see preliminary results and appended manuscript). Non-Hodgkin's lymphoma (NHL) is the 5th most common cancer in the U.S. and accounts for 5% of all cancer- related deaths per year. The 5-year cure rate is only 50%. These tumors are known to express significant amounts of the CD74 antigen. NHL might best respond to a specific targeting approach using a drug-AB conjugate, due to its widely disseminated nature and the relative accessibility of cancer cells to systemically administered agents. In addition, the greater inherent sensitivity of hematopoietic tumors, the natural course of this disease with cells growing out of control and terminally outnumbering normal B cells, offers the chance of delivering a much higher . ratio of injected drug-Ab specifically to diseased cells, as compared to normal cells. This proposal will therefore address the utility of an LL1-Dox immunoconjugate for treatment of disseminated NHL using several established preclinical models and primary NHL biopsy specimens. We will also address several novel biological questions including (a) the possibility of overcoming multidrug resistance (typically expressed by ~60% of refractory NHL patients) by delivering Dox directly with an antibody, and (b) overcoming cardiotoxicity associated with the administration of free doxorubicin.