Background.The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition.Objectives/Methods.In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL).Results.The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8+tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model.Conclusions.These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors.
背景：实体瘤中富含透明质酸（HA）的致密基质会阻碍药物递送和免疫细胞浸润，从而影响有效的肿瘤生长抑制。然而，仅通过全身递送透明质酸酶降解HA并未显著改善肿瘤生长抑制效果。目的/方法：本研究通过将抗体与重组人透明质酸酶（HYAL）融合，构建抗体-酶（AbEn）分子，以实现靶向透明质酸降解。结果：AbEn分子稳定性良好，同时保留了抗原结合活性和酶活性，在啮齿动物模型中表现出长达132小时的血清半衰期。在富含HA的结直肠癌模型中，靶向癌症相关成纤维细胞（CAF）的AbEn分子TAVO423（FAP × LRRC15 × HYAL三特异性抗体）相较于非靶向HYAL，实现了更强的瘤内HA清除，从而获得更优的肿瘤生长抑制效果。此外，TAVO423联合其他实体瘤靶向治疗方式（如5-氟尿嘧啶（5-FU）、抗PD-L1单克隆抗体、PD-L1 × CD3双特异性T细胞衔接器（TCE）以及靶向CD318的抗体偶联药物（ADC））均显示出增强的肿瘤生长抑制（TGI）效果，联合治疗的TGI值达49–67%，而相应单药治疗的TGI值仅为1–28%。在体内富含HA的胰腺癌模型中，TAVO423还改善了5T4 × CD3 TCE的抗肿瘤反应，使TGI从73%提升至92%。TAVO423介导的CAF靶向HA降解还能逆转免疫排斥，在免疫正常的EMT-6乳腺癌体内模型中使CD8+肿瘤浸润淋巴细胞（TILs）密度增加6–9倍，并与PD-1阻断协同作用，将TGI从33%提高至51%。结论：这些发现证明了模块化AbEn平台在靶向HA降解方面的广泛潜力，可用于克服富含HA基质的实体瘤中的屏障问题。
Targeted Hyaluronan Degradation Enhanced Tumor Growth Inhibition in Gastrointestinal Cancer Models
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