Recently, Innovent and Remegen announced a cooperation agreement on clinical research and drug supply, that is they will carry out a clinical research cooperation on the combination of Sintilimab Injection, a PD-1 inhibitor, with RC88, a novel antibody-drug conjugate (ADC) targeting MSLN, and RC108, a novel ADC targeting c-MET, respectively. Based on the cooperation agreement, Innovent will provide the Sintilimab Injection used for the trial, and Remegen will perform a Phase 1/2a clinical research in China to evaluate the safety, tolerability and preliminary efficacy of Sintilimab Injection combined with RC88 or RC108 in Chinese tumor patients.

RC88 is an ADC targeting MSLN developed by Remegen. The results of preclinical research show that after binding with MSLN on the surface of tumor cells, the product enters the cells through endocytosis, releases small molecules through protease cleavage, and plays a killing role to block tumor cells in Phase G2/M and induce tumor cell apoptosis. RC88 combined with PD-1/L1 and other immune checkpoint inhibitors can induce the death of immunogenic cells, release a series of signal molecules to further activate T cells, enhance tumor immune response, and synergistically produce a stronger anti-tumor effect. RC88 has been approved to perform Phase I clinical trial in China. At present, the trial is in progress, and the preliminary results show that the single-drug of the product has anti-tumor activity against solid tumors expressed by MSLN, with a controlled safety. In this March, the open and multi-center Phase I/IIa clinical research, which studies the safety, tolerance, pharmacokinetic characteristics and curative effect of RC88 combined with Toripalimab Injection on the patients with advanced malignant solid tumors, was officially approved by the Center for Drug Evaluation of NMPA.

RC108 is an ADC targeting c-MET developed by Remegen. The results of preclinical research show that the product can induce tumor specific and adaptive immunity and increase the infiltration of T cells into tumor microenvironment, while anti-PD-1 monoclonal antibody can activate T cells and enhance anti-tumor immune response. Thus, it is expected that RC108 combined with Sintilimab can enhance the presentation of dendritic cells to tumor antigens and enhance the killing of T cells to tumor cells to produce enhanced synergistic tumor suppression effect. The product was approved for the Phase I clinical trial on the c-Met positive advanced solid tumors in China in November, 2020. At present, the trial is in progress smoothly, and the preliminary results show that the single-drug of RC108 has anti-tumor activity against solid tumors expressed by c-MET, with a controlled safety.

The mechanism of action of PD-1 combined with ADC

Tumors are also divided into "hot and cold", which can be distinguished by the content of immune cells in tumor tissue (The confrontation degree between tumor cells and immune cells, the core index of which is the infiltration degree of T cells into tumors).

The hot tumors can make an inhibition on the T cells because of the binding of high expressed PD-L1 and PD-1 receptor, thus the immunotherapy led by PD-1 inhibitor has a better effect; The cold tumor is called as "immune desert" in the industry because of the few or no T lymphocytes, thus the immunotherapy can not have its due effect. 

This also explains to some extent why PD-1 monotherapy has an immune response in only 30% patients with most cancer types. In order to improve the response rate of tumor cells in patients, from the perspective of PD-1 combination strategy, the best combination is the drug that can "heat" the tumor.

ADC has the ability to "heat" tumors. According to the clinical trial data of TDM1 combined with PD-1 and CTLA-4, the agonist in ADC can trigger innate immunity and acquired immunity and infiltrate lots of T cells into the tumor to improve the effect of immunotherapy. 

The R&D of PD-1 inhibitor combined with ADC in China

Remegen, as the leader of ADC in China, is exploring many indications of Disitamab Vedotin combined with Junshi Biosciences' Toripalimab at present. At the 2022 ASCO, Remegen disclosed the data of Phase I/II of Disitamab Vedotin combined with Toripalimab on the first-line treatment of urothelial carcinoma. There are 39 subjects involved in the research, and the ORR is 71.8% and mPFS is 9.2m for the combination therapy, which the data is quite outstanding, and even has the potential to surpass the Keytruda combined with Padcev.

Kelun Pharmaceutical, a rising star in the ADC field, has no ADC approved for marketing, but has products with over US$10 billion which have gone abroad successfully, which has already started the signboard. SKB264, a kind of TROP2 ADC, combined with KL-A167 (PD-L1 monoclonal antibody) for the first-line treatment of mTNBC and for the treatment of advanced NSCLC is in the Phase II clinical stage. KL-A167 is also a PD-L1 monoclonal antibody with independent intellectual property rights from Kelun Biotech.

As an innovative drug leader enterprise in China, Hengrui Pharmaceuticals has been eager to try ADC+PD-1. However, what is explored firstly by Hengrui is "ADC + bispecific antibody". On October 21, 2022, the research for Hengrui Pharmaceuticals' SHR-A1811, a kind of ADC targeting HER2, combined with SHR-1701, a kind of bifunctional fusion protein of PD-L1/TGF-β, on treating the HER2 positive advanced gastric cancer was approved for clinical. In this March, Hengrui also registered a Camrelizumab-related clinical research for treating triple negative breast cancer, involving the combination of SHR-A1811 and Camrelizumab.

With the tumor immunotherapy entering the next stage, it is expected that the combination therapy of PD-1 inhibitor and new drug of ADC will bring us a new opportunity to potentially enhance patients' benefits and overcome tumor resistance.

Reference

1. Official website of Remegen

2. Official website of Innovent

3. Official website of Kelun Biotech

4. Official website of CDE

5. A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. J. Immunother. Cancer, 7 (2019), p.16