The approval of sintilimab for classical Hodgkin's lymphoma: views and perspectives of anti-PD-1/PD-L1 antibodies in China

Statement of Significance

With the recent approval of Sintilimab for the treatment of classic Hodgkin's lymphoma in China, totally four anti-PD-1 antibodies have been approved by the National Medical Products Administration of China (NMPA) for cancer immunotherapy.

It has been well established that the use of immunotherapy can improve the survival of patients with cancer and, in some cases, achieve complete remission. The monoclonal antibody against the programmed cell death protein 1 (PD-1) has been the most studied among known immune checkpoint inhibitors in diverse types of human cancer and consistently demonstrated therapeutic efficacy in many conditions. Currently, four anti-PD-1 antibodies have been approved by the National Medical Products Administration of China (NMPA) for the clinical use in China, as summarized in Table 1.

Table 1.

Approved anti-PD-1 therapeutic antibodies in China

Product name	Generic name	Approved date	Indication	Company
Opdivo	Nivolumab	06/15/2018	NSCLC	Bristol-Myers Squibb
Keytruda	Pembrolizumab	07/25/2018	Melanoma	Merck & Co.
Tuoyi	Toripalimab	12/17/2018	Melanoma	Shanghai Junshi Biosciences
Tyvyt	Sintilimab	12/27/2018	cHL	Innovent Biologics

Note: NSCLC, Non-small cell lung cancer; cHL, classic Hodgkin's lymphoma.

The developers of the four approved anti-PD-1 antibodies are two international big pharmaceutical companies (Bristol-Myers Squibb, New York City, NY, and Merck & Co., Kenilworth, NJ) and two Chinese companies (Shanghai Junshi Biosciences, Shanghai, China and Innovent Biologics, Suzhou, China). The latest approved anti-PD-1 antibody is sintilimab, which was developed by Innovent Biologics (Fig. 1) for the indication of refractory classic Hodgkin's lymphoma (cHL), which is largely an unmet medical need in China. A single-arm phase 2 clinical trial study (NCT031146833) recently reported in The Lancet Haematology demonstrated that the overall response rate was 80.4% and the disease control rate was 97.8%, respectively [1]. Sintilimab achieved 77.6% of progression-free survival at 6 months for patients with cHL [1], and the efficacy appears to be comparable to that of nivolumab (77%) and pembrolizumab (69%) [2, 3]. Dr. Michael Yu, the chairman, CEO and president of Innovent Biologics, commented that sintilimab, a novel full human IgG4 antibody targeting PD-1 generated by yeast display method, has 10–50 folds higher binding affinity to PD-1 than nivolumab and pembrolizumab [4] and pharmacodynamics analysis in cHL patients showed greater than 95% PD-1 receptor occupancy [1]. Based on the data of crystal structure of sintilimab/PD-1 complex [4], sintilimab appears to bind to PD-1 in a unique conformational epitope with highly complementary, hydrophobic surfaces formed by antibody complementarity-determining regions (CDRs), distinct from nivolumab and pembrolizumab. The area of the interactive hydrophobic surfaces on sintilimab is almost double those on nivolumab or pembrolizumab, with seven cluster-distributed alkyl–π interactions identified when bound to PD-1. These characteristics confer a significantly slower off-rate to sintilimab compared to nivolumab or pembrolizumab. Moreover, high rates of CD8⁺ T cells vs. T_reg cells and CD8⁺ T vs. CD4⁺ T cells were observed in both preclinical mouse model [5] and human subjects and improved the ratio of effector T cell populations that may contribute to the mechanism of action of sintilimab.

Figure 1.

The PD-1 antibody sintilimab.

Similar to US and European markets where six anti-PD-1/PD-L1 antibodies have been approved, PD-1/PD-L1 checkpoint drugs are also rapidly entering market in China. Ind addition to the four approved anti-PD-1 antibodies listed above, tislelizumab (BeiGene, Beijing, China) and camrelizumab (Jiangshu HengRui Medicine, Lianyungang, China) are in late-stage clinical studies for cancer indications [6], and two anti-PD-L1 antibodies, durvalumab (AstraZeneca, Wilmington, DE) and atezolizumab (Roche, Basel, Switzerland), are currently under review with NMPA for the new drug applications in China. Moreover, at least a dozen other Chinese companies are developing their own anti-PD-1/PD-L1 therapeutic antibodies, which are either in early-stage clinical trials or at the investigational new drug (IND) stage.

In order to compete with the well-established international pharmaceutical companies such as Bristol-Myers Squibb, Merck, AstraZeneca and Roche, Chinese pharmaceutical companies have to become more competitive by developing more innovative drugs that could overcome current major challenges of immune-oncology (I-O) therapies including low response rate, drug resistance, unclear mechanism of actions of combinational therapies, clinical trial design and increasing patient cost. Combination therapy of checkpoint inhibitors can be a good strategy to generate synergism and render resistant tumor to treatment amenable one. In addition to combination of chemotherapy and oncolytic virus, the bi-specific antibodies can become the next frontier of I-O therapies. According to Dr. Yu, recent preclinical data on a novel bi-specific antibody (IBI318) targeting PD-1 and a tumor-associate antigen (non-disclosed target) showed significant inhibition of tumor progression by combination of inhibition of immune checkpoint in T cells, blockade of cellular signaling in tumor cells and, more importantly, increase of T cell killing of tumor cells by potentiate immune synapse between the two cell types. This bi-specific antibody (IBI318) was just approved in early February in China for a clinical trial, and the bi-specific antibody approach could become a promising next-generation anti-PD-1 antibody therapy.