Recent Advances in PARP Inhibitor Bispecific Antibody Hotspots

In the AACR inventory on April 3, WuXi PharmaTech's WeChat team will share the latest developments in three hotspot research areas, namely “unlimited cancer” targeted drug development, PARP inhibitors, and bispecificity. antibody.

In 2018, Loxo Oncology's "unlimited cancer" targeted therapy Vitrakvi received FDA approval, becoming the first cancer-free, targeted therapy for patients with NTRK gene fusion variant solid tumors. Loxo has begun to develop a new generation of TRK inhibitors before Vitrakvi was approved. Although Vitrakvi acts as a TRK inhibitor, it achieves a 75% response rate in patients with solid tumors, but over time, tumors acquire genetic mutations that are resistant to TRK inhibitors, so development can be effective against these tumors. A new generation of inhibitors is an urgent task.

On April 2, Bayer announced the results of an early clinical trial of the new generation of TRK inhibitor LOXO-195 developed by Loxo. Bayer acquired the exclusive R&D rights of LOXO-195 after Loxo's acquisition by Lilly. LOXO-195 is capable of inhibiting the activity of TRK proteins that have developed resistance to existing TRK inhibitors. The results of the trial showed that LOXO-195 achieved an objective response rate (ORR) of 45% in 20 patients with solid tumors who had received a TRK inhibitor and were resistant to it. Although this study is still in its early clinical stage, it suggests that LOXO-195 may help address the unmet medical needs of patients with solid tumors that are resistant to existing TRK inhibitors.

PARP inhibitors are a class of drugs that treat tumors that are defective in BRCA gene mutations or homologous recombinant antibody DNA repair mechanisms by a "synthesis-killing" mechanism. They have shown excellent efficacy in the treatment of ovarian and breast cancer. Recent studies have shown that these drugs can also be used in cancer types other than breast cancer. In February 2019, Lystraza developed by AstraZeneca and Merck (MSD) as a maintenance therapy reached the primary end point in phase 3 clinical trials for the treatment of pancreatic cancer. At the AACR conference on April 3, Clovis's PARP inhibitor Rubraca also obtained positive data in Phase 2 clinical trials for the treatment of pancreatic cancer.

In a one-arm phase 2 clinical trial enrolling 42 patients with advanced pancreatic cancer, Rubaraca served as a first-line maintenance therapy for patients who had received platinum-based chemotherapy and had no progression of disease over the past four months. These patients carry mutations in the pathogenic germline or somatic BRCA1, BRCA2 or PALB2 genes.

Interim data analysis showed a median progression-free survival (PFS) of 9.1 months in 19 patients who were able to be evaluated. Of these 19 patients, one patient achieved complete remission and six patients achieved partial remission. These patients carried germline BRCA2 gene mutations (n=4), germline PALB2 gene mutations (n=2), and somatic BRCA2 gene mutations (n=1).

These preliminary data, combined with Phase 3 data from Lynparza, suggest that PARP inhibitors may provide a new treatment modality for advanced pancreatic cancer. Approximately 5-8% of patients with pancreatic cancer carry a BRCA1, BRCA2 or PALB2 pathogenic mutation.

Epitope specific Antibody and multispecific antibodies are becoming a new model of cancer treatment. At the AACR conference, Inovio announced preclinical data on the company's innovative DNA-encoded bispecific T cell adapter (dBiTE). One end of the bispecific TCR adapter (BiTE) can bind to the specific antigen on the surface of the tumor, while the other end can bind to the CD3 receptor on the surface of the T cell, and recruit T cells around the tumor to kill the tumor cells. effect.

One of the challenges faced by BiTE-type proteins is that the stability of these proteins is not high, leading to the need for patients to receive frequent treatment. Inovio's innovative strategy is to introduce DNA encoding the BiTE protein into human cells, making the somatic cells a "factory" for the production of BiTE, thus continuing to provide BiTE proteins.

Preclinical studies published in the AACR show that the DOBI-targeted dBiTE developed by Inovio maintains high levels of BiTE protein expression in mice for 4 months after one treatment in a mouse model of breast and ovarian cancer. Moreover, dBiTE targeting HER2 is effective in stimulating the cytotoxicity of T cells to HER2-expressing tumor cells, resulting in near complete tumor clearance.