人4-1BBL/抗CD20融合蛋白增强抗CD3/抗CD20双功能抗体的细胞毒作用及其机制研究
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摘要
目前,①常规的放、化疗方案选择性较差；②肿瘤细胞产生耐药性；③肿瘤发生微小转移是困扰肿瘤的临床治疗三大难题,双功能抗体或融合蛋白因其具有同时与肿瘤相关抗原和免疫效应细胞表面分子标记结合,并能有效地使效应细胞靶向杀灭肿瘤细胞的作用而倍受关注,最有希望成为解决这些问题的一条新途径。
在抗肿瘤免疫反应中,细胞介导的免疫反应起着重要作用。肿瘤免疫治疗的目标就是产生肿瘤特异性的具有长期持续性杀伤活性的激活的CD8+T细胞。初始T细胞的完全激活需要双重信号刺激,即T细胞受体与抗原肽-MHC分子复合物结合的第一信号,又必须有T细胞和抗原提呈细胞表面多种共刺激分子相互作用提供的共刺激信号即第二信号。T细胞激活诱导阶段若缺乏共刺激信号,会引起T细胞通过活化诱导的细胞死亡途径凋亡和克隆特异性无反应性,进而导致抗肿瘤免疫功能低下,而通过低表达共刺激分子降低免疫原性,使得识别它的抗原提呈细胞或淋巴细胞得不到充分的活化信号,是肿瘤细胞免疫逃逸的重要机制之一,临床实践中,这类肿瘤的治疗效果和预后不佳。共刺激信号途径在T细胞的活化和增殖过程中起着重要作用。CD28／B7分子是研究最多的协同刺激分子,认为是初始T细胞激活发生最主要的机制,然而,近来研究的4-1BB／4-1BBL是TNFR／TNF配体家族的成员,它们分别表达在T细胞和抗原提呈细胞上,被确定有助于扩增和多元化T细胞反应,深入增强和延伸T细胞激活的功能,许多动物实验表明干预4-1BB／4-1BBL共刺激途径可调节T细胞和抗原呈递细胞的功能产生抗肿瘤免疫作用,为肿瘤的免疫治疗提供了新的靶点。
CD20主要表达在前B细胞和成熟B细胞及95%以上的NHL淋巴瘤细胞,是可以用来作为肿瘤定向免疫治疗的抗原。为了特异性定向肿瘤细胞和激活肿瘤特异性T细胞,抗肿瘤免疫性能够被诱导和恢复,利用双特异抗体针对肿瘤相关抗原与效应细胞相连,共同作用于肿瘤细胞,实现肿瘤的靶向治疗,我们已成功构建了抗CD3／抗CD20的diabody表达载体和人4-1BBL胞外区基因表达载体pAYZ4-1BBL并进行了体内外生物活性测定,前者有的抑制肿瘤生长的活性而后者则能抑制激活的T细胞凋亡,增强基于PBL的抗肿瘤效应。然而全身性的T细胞激活将导致不需要的临床副作用,应用4-1BBL和CD3单克隆抗体可代替专职抗原提呈细胞的刺激能力,因此基于4-1BBL和CD3双信号所必须严格定位在肿瘤位点,本实验在此基础上构建了人4-1BBL胞外区／抗CD20融合蛋白,获得可溶性表达在2-3mg／l,流式间接免疫荧光实验及玫瑰花环实验均证实了人4-1BBL胞外区／抗CD20融合蛋白具有与CD20+的Raji细胞和4-1BB+的Jurkat细胞结合活性。研究结果表明人4-1BBL胞外区／抗CD20融合蛋白能增强抗CD3／抗CD20 diabody介导PBLs对靶细胞Raji细胞的杀伤作用,其机制是上调抗凋亡相关基因bcl-xL和bfl-1mRNA的表达,促进淋巴细胞增殖,减少细胞死亡,促进IL-2分泌及上调穿孔素和颗粒酶mRNA表达,更有效导致PBLs杀伤肿瘤细胞。应用裸鼠移植瘤模型也表明联合应用人4-1BBL／CD20融合蛋白和抗CD20diabody能明显抑制肿瘤生长,这充分说明基于4-1BBL和CD3双信号作用能更有效地激发PBLs的活性,从而清除肿瘤。
因此,人4-1BBL胞外区／抗CD20融合蛋白作为一种靶向性免疫调节融合蛋白,能够调节PBL的活化程度,进而增强基于PBL的靶向性的抗肿瘤治疗的效果,是一个有望用于B细胞恶性肿瘤临床治疗的特异性融合蛋白。
The three main drawbacks in conventional chemotherapy and radiotherapy of cancer are the lack of specificity of the currently available therapeutic agents, multidrug resistance of tumor cells and tumor micrometastases. So, antibodies represent a unique class of new therapeutics owing to their high specificity for a defined antigen. Recent clinical success with antibody-based therapeutics has led to an upsurge in the development of these agents. Bispecific antibodies, with one binding arm to surface markers on tumor cells and the other to molecules on effector cells, represent an alternative approach to the conventional antibody-based cancer therapeutics
Cell-mediated responses play a central role in antitumor immunity. The aim of tumor immunotherapy has been to generate long-lasting functionally active CD8+ T cells specific for the tumor cells. In order to activate a naive T cell, two signals are thought to be requisite.The primary signal or signal one occurs through the TCR:MHC:Ag (antigen) complex while the second signal or signal two is provided through costimulation. If costimulatory signal was not served to activated T lymphocyte, T cell may lead to activation induced cell death (AICD) or annergy which finally impair antitumor immunity. Tumor cells often expressed low level of costimulatory molecules to provide insufficient signals to antigen presenting cells or lymphocytes, hence to escape immunosurveilence. Such kind of tumors usually manifestated poor therapeutic outcomes and prognosis.Therefore, costimulatory pathway in T cell activation and proliferation plays an important role. CD28/B7 pathway is one of the most importment costimulatory pathways that promote the naive T cell activation. However, a number of molecules have been identified which function to further enhance and extend the activation of T cells. These include the more recently described 4-1BB/4-1BB ligand (4-1BBL) molecules that regulate T cell activation by means of increasing cell proliferation, prolonging cell survival, even increase the intracellular storage of perforin and granule enzyme. All of these characters provide a new target in cancer immunotherapy.
The CD20 antigen is an attractive target for specific treatment of B-cell lymphoma as it is expressed in pre-B cells, mature B cells and more than 95% of B-cell lymphoma. To specifically target B-cell lymphoma via the TAA CD20, we before engineered a bispecific diabody recognizing the CD3-TCR complex, as well as CD20 (anti-CD3/anti-CD20 diabody) and constructed the human extracellular domain of 4-1BBL(ex4-1BBL). They can be used not only to redirect preactivated cytotoxic T cells toward the tumor, but, moreover, are able to stimulate resting or even anergic T cells if sufficient costimulatory signaling (for example, via the 4-1BB/4-1BBL pathway) is provided. Artificial signaling via the CD3 antigen mimicks the physiological antigen-specific activation of T lymphocytes by MHC-bound antigen. On the other hand. The simultaneous use of CD3 and 4-1BB monoclonal antibodies may, thus, substitute for the T-cell stimulatory capacity of professional antigen-presenting cells. However, to avoid a systemic T-cell activation that may result in undesirable clinical side effects, the CD3/4-1BB signaling has to be localized strictly to the tumor site. To provide tumor-specific 4-1BB costimulation, here we constructed and produced a recombinant human 4-1BB ligand (4-1BBL) /anti-CD20 fusion protein and examined its antitumor activity, alone and in combination with an anti-CD3/anti-CD20 bispecific diabody. The 4-1BBL/anti-CD20 fusion protein retained both the costimulatory activity of 4-1BBL on T cells and the tumor-targeting ability of CD20 antibody on B cells. The fusion protein bound as efficiently to 4-1BB- and CD20-positive cells as its respective parental antibodies, and was capable of cross-linking human T lymphocytes and CD20-positive tumor cells. We continued to identify that combination treatment with the 4-1BBL/anti-CD20 fusion protein and the anti-CD3/anti-CD20 diabody led to significantly increased T cell cytotoxicity to human B lymphoma cells in vitro and drastically more potent tumor inhibitory activity in vivo in xenografted B-cell lymphoma in SCID mice. Mechanistic studies revealed that the combination treatment remarkably inhibited apoptosis of human peripheral blood lymphocytes, accompanied by up-regulation of Bcl-xL and Bf1-1, perforin and granzyme B mRNA and increased IL-2 production.
Our results demonstrated that 4-1BBL/CD20, as a targeted immunoadjuvant, can modulate the PBL activation and enhance the outcomes of PBL-based antitumor biotherapy. The combined administration of 4-1BBL/CD20 and diabody could strongly potentiate the antitumor activity of the diabody, thus may have significant clinical application in the treatment of human CD20-positive B cell malignancies.
在抗肿瘤免疫反应中,细胞介导的免疫反应起着重要作用。肿瘤免疫治疗的目标就是产生肿瘤特异性的具有长期持续性杀伤活性的激活的CD8+T细胞。初始T细胞的完全激活需要双重信号刺激,即T细胞受体与抗原肽-MHC分子复合物结合的第一信号,又必须有T细胞和抗原提呈细胞表面多种共刺激分子相互作用提供的共刺激信号即第二信号。T细胞激活诱导阶段若缺乏共刺激信号,会引起T细胞通过活化诱导的细胞死亡途径凋亡和克隆特异性无反应性,进而导致抗肿瘤免疫功能低下,而通过低表达共刺激分子降低免疫原性,使得识别它的抗原提呈细胞或淋巴细胞得不到充分的活化信号,是肿瘤细胞免疫逃逸的重要机制之一,临床实践中,这类肿瘤的治疗效果和预后不佳。共刺激信号途径在T细胞的活化和增殖过程中起着重要作用。CD28／B7分子是研究最多的协同刺激分子,认为是初始T细胞激活发生最主要的机制,然而,近来研究的4-1BB／4-1BBL是TNFR／TNF配体家族的成员,它们分别表达在T细胞和抗原提呈细胞上,被确定有助于扩增和多元化T细胞反应,深入增强和延伸T细胞激活的功能,许多动物实验表明干预4-1BB／4-1BBL共刺激途径可调节T细胞和抗原呈递细胞的功能产生抗肿瘤免疫作用,为肿瘤的免疫治疗提供了新的靶点。
CD20主要表达在前B细胞和成熟B细胞及95%以上的NHL淋巴瘤细胞,是可以用来作为肿瘤定向免疫治疗的抗原。为了特异性定向肿瘤细胞和激活肿瘤特异性T细胞,抗肿瘤免疫性能够被诱导和恢复,利用双特异抗体针对肿瘤相关抗原与效应细胞相连,共同作用于肿瘤细胞,实现肿瘤的靶向治疗,我们已成功构建了抗CD3／抗CD20的diabody表达载体和人4-1BBL胞外区基因表达载体pAYZ4-1BBL并进行了体内外生物活性测定,前者有的抑制肿瘤生长的活性而后者则能抑制激活的T细胞凋亡,增强基于PBL的抗肿瘤效应。然而全身性的T细胞激活将导致不需要的临床副作用,应用4-1BBL和CD3单克隆抗体可代替专职抗原提呈细胞的刺激能力,因此基于4-1BBL和CD3双信号所必须严格定位在肿瘤位点,本实验在此基础上构建了人4-1BBL胞外区／抗CD20融合蛋白,获得可溶性表达在2-3mg／l,流式间接免疫荧光实验及玫瑰花环实验均证实了人4-1BBL胞外区／抗CD20融合蛋白具有与CD20+的Raji细胞和4-1BB+的Jurkat细胞结合活性。研究结果表明人4-1BBL胞外区／抗CD20融合蛋白能增强抗CD3／抗CD20 diabody介导PBLs对靶细胞Raji细胞的杀伤作用,其机制是上调抗凋亡相关基因bcl-xL和bfl-1mRNA的表达,促进淋巴细胞增殖,减少细胞死亡,促进IL-2分泌及上调穿孔素和颗粒酶mRNA表达,更有效导致PBLs杀伤肿瘤细胞。应用裸鼠移植瘤模型也表明联合应用人4-1BBL／CD20融合蛋白和抗CD20diabody能明显抑制肿瘤生长,这充分说明基于4-1BBL和CD3双信号作用能更有效地激发PBLs的活性,从而清除肿瘤。
因此,人4-1BBL胞外区／抗CD20融合蛋白作为一种靶向性免疫调节融合蛋白,能够调节PBL的活化程度,进而增强基于PBL的靶向性的抗肿瘤治疗的效果,是一个有望用于B细胞恶性肿瘤临床治疗的特异性融合蛋白。
The three main drawbacks in conventional chemotherapy and radiotherapy of cancer are the lack of specificity of the currently available therapeutic agents, multidrug resistance of tumor cells and tumor micrometastases. So, antibodies represent a unique class of new therapeutics owing to their high specificity for a defined antigen. Recent clinical success with antibody-based therapeutics has led to an upsurge in the development of these agents. Bispecific antibodies, with one binding arm to surface markers on tumor cells and the other to molecules on effector cells, represent an alternative approach to the conventional antibody-based cancer therapeutics
Cell-mediated responses play a central role in antitumor immunity. The aim of tumor immunotherapy has been to generate long-lasting functionally active CD8+ T cells specific for the tumor cells. In order to activate a naive T cell, two signals are thought to be requisite.The primary signal or signal one occurs through the TCR:MHC:Ag (antigen) complex while the second signal or signal two is provided through costimulation. If costimulatory signal was not served to activated T lymphocyte, T cell may lead to activation induced cell death (AICD) or annergy which finally impair antitumor immunity. Tumor cells often expressed low level of costimulatory molecules to provide insufficient signals to antigen presenting cells or lymphocytes, hence to escape immunosurveilence. Such kind of tumors usually manifestated poor therapeutic outcomes and prognosis.Therefore, costimulatory pathway in T cell activation and proliferation plays an important role. CD28/B7 pathway is one of the most importment costimulatory pathways that promote the naive T cell activation. However, a number of molecules have been identified which function to further enhance and extend the activation of T cells. These include the more recently described 4-1BB/4-1BB ligand (4-1BBL) molecules that regulate T cell activation by means of increasing cell proliferation, prolonging cell survival, even increase the intracellular storage of perforin and granule enzyme. All of these characters provide a new target in cancer immunotherapy.
The CD20 antigen is an attractive target for specific treatment of B-cell lymphoma as it is expressed in pre-B cells, mature B cells and more than 95% of B-cell lymphoma. To specifically target B-cell lymphoma via the TAA CD20, we before engineered a bispecific diabody recognizing the CD3-TCR complex, as well as CD20 (anti-CD3/anti-CD20 diabody) and constructed the human extracellular domain of 4-1BBL(ex4-1BBL). They can be used not only to redirect preactivated cytotoxic T cells toward the tumor, but, moreover, are able to stimulate resting or even anergic T cells if sufficient costimulatory signaling (for example, via the 4-1BB/4-1BBL pathway) is provided. Artificial signaling via the CD3 antigen mimicks the physiological antigen-specific activation of T lymphocytes by MHC-bound antigen. On the other hand. The simultaneous use of CD3 and 4-1BB monoclonal antibodies may, thus, substitute for the T-cell stimulatory capacity of professional antigen-presenting cells. However, to avoid a systemic T-cell activation that may result in undesirable clinical side effects, the CD3/4-1BB signaling has to be localized strictly to the tumor site. To provide tumor-specific 4-1BB costimulation, here we constructed and produced a recombinant human 4-1BB ligand (4-1BBL) /anti-CD20 fusion protein and examined its antitumor activity, alone and in combination with an anti-CD3/anti-CD20 bispecific diabody. The 4-1BBL/anti-CD20 fusion protein retained both the costimulatory activity of 4-1BBL on T cells and the tumor-targeting ability of CD20 antibody on B cells. The fusion protein bound as efficiently to 4-1BB- and CD20-positive cells as its respective parental antibodies, and was capable of cross-linking human T lymphocytes and CD20-positive tumor cells. We continued to identify that combination treatment with the 4-1BBL/anti-CD20 fusion protein and the anti-CD3/anti-CD20 diabody led to significantly increased T cell cytotoxicity to human B lymphoma cells in vitro and drastically more potent tumor inhibitory activity in vivo in xenografted B-cell lymphoma in SCID mice. Mechanistic studies revealed that the combination treatment remarkably inhibited apoptosis of human peripheral blood lymphocytes, accompanied by up-regulation of Bcl-xL and Bf1-1, perforin and granzyme B mRNA and increased IL-2 production.
Our results demonstrated that 4-1BBL/CD20, as a targeted immunoadjuvant, can modulate the PBL activation and enhance the outcomes of PBL-based antitumor biotherapy. The combined administration of 4-1BBL/CD20 and diabody could strongly potentiate the antitumor activity of the diabody, thus may have significant clinical application in the treatment of human CD20-positive B cell malignancies.
引文
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