Guide: Tongyi Pharmaceutical's Global First-in-Class Bispecific Ligand Conjugate (Bi-XDC)
Recently, Tongyi Pharmaceutical's first bispecific small molecule drug conjugate, CBP-1008 (Rico-V), received approval from China's NMPA to initiate a Phase III clinical trial for platinum-resistant ovarian cancer (PROC).
As reported, this fully chemically synthesized bispecific ligand conjugate (Bi-XDC) has a molecular weight approximately 1/50 that of traditional ADC drugs, offering unique advantages in CMC (Chemistry, Manufacturing, and Controls) and treatment costs. The approval of Rico-V for the Phase III registration trial marks a significant step toward becoming the world's first Bi-XDC drug, promising a new therapeutic option for ovarian cancer patients.
Novel Therapy Overcomes the "King of Gynecological Cancers"
Ovarian cancer ranks first in mortality among gynecological malignancies, earning it the title of the "king of gynecological cancers." Often called the "silent killer" due to its lack of specific early symptoms, it is frequently diagnosed at an advanced stage.
According to 2024 statistics from China's National Cancer Center, there are approximately 61,100 new ovarian cancer cases and 32,600 deaths annually in China, with about 70% of patients diagnosed at an advanced stage. Current standard treatments include surgery combined with platinum-based chemotherapy ± targeted maintenance therapy, but most patients relapse and develop platinum resistance. Platinum-resistant ovarian cancer (PROC) has a poor prognosis and extremely limited treatment options.
While some innovative drugs have been approved recently-such as AbbVie's FRα ADC drug ELAHERE® (sacituzumab govitecan-hziy)-the unmet treatment needs of PROC patients remain substantial.
CBP-1008 brings hope to this dilemma. Developed based on Tongyi Pharmaceutical's proprietary Bi-XDC platform, it is the world's first bispecific ligand conjugate, simultaneously targeting FRα and TRPV6 receptors expressed on tumor cell membranes.
Clinical data released by Tongyi Pharmaceutical shows significant efficacy of CBP-1008 in PROC patients who received 1-3 prior lines of treatment. The median overall survival (mOS) reached 19.4 months (N=163), surpassing historical data for single-agent chemotherapy (≤3 lines of PROC) at 10.9-13.9 months and sacituzumab govitecan-hziy at 15.6-16.5 months.Notably, it remains effective in patients with low folate receptor expression, independent of folate expression levels.
In terms of safety, most adverse events (AEs) are mild to moderate. Unlike other antibody-drug conjugates (ADCs) using monomethyl auristatin E (MMAE) as the payload, Rico-V shows no significant ocular toxicity or peripheral neurotoxicity, which are common with such ADCs.
In production and supply, Rico-V, as a fully chemically synthesized small bispecific conjugate, has a molecular weight about 1/50 that of traditional ADCs. Its advantages in CMC-including simple synthesis/preparation, defined chemical structure, and easy control of production processes and quality indicators-result in significantly lower production and treatment costs compared to ADC drugs.
The NMPA's approval of CBP-1008 for the Phase III registration trial in PROC represents a crucial step toward clinical application, potentially providing a new treatment approach for platinum-resistant ovarian cancer patients.
Bi-XDC: The Next-Generation Conjugate Star
Traditional targeted chemotherapy drugs in clinical oncology suffer from low targeting, high side effects, easy development of drug resistance, and high recurrence rates. ADCs (Antibody-Drug Conjugates) combine traditional chemotherapy drugs with recombinant monoclonal antibodies via linkers, endowing chemotherapy drugs with active targeting capabilities for precise cancer treatment.
However, ADCs, as large-molecule biologics, face challenges such as complex production processes, high treatment costs, and suboptimal clinical safety.
Tongyi Pharmaceutical has developed a novel technology-bispecific ligand conjugates (Bi-XDC)-pioneering a new path in drug development.
A Bi-XDC molecule consists of four components: Ligand A targeting Receptor 1, Ligand B targeting Receptor 2, a therapeutic payload, and a linker. Through the synergistic interaction of two ligands with surface receptors on target tumor cells, Bi-XDC precisely delivers the conjugated payload to specific cells.
Compared to traditional ADCs, Bi-XDC drugs offer advantages such as broader target coverage, lower toxicity, and lower costs (enabling full chemical synthesis). On one hand, the pairing of bispecific ligands enhances target specificity and affinity, transforming two undruggable single targets into a druggable bispecific pair, thus enabling targeting of more previously undruggable targets. On the other hand, Bi-XDC maintains a relatively small molecular weight (about 1/50 that of ADCs), allowing faster cellular uptake and clearance from non-lesional tissues, significantly improving efficacy and safety.
Currently, Tongyi Pharmaceutical has three Bi-XDC products in clinical stages: CBP-1008, CBP-1018, and CBP-1019, covering high-need areas such as ovarian cancer, prostate cancer, and endometrial cancer.
Small molecules (e.g., folic acid, biotin, lactic acid, glycyrrhetinic acid) are easily accessible, cost-effective, low-toxic, free of immune stress, and readily characterizable and modifiable, making them widely used as targeting moieties in active targeted therapy for anticancer drugs.
Folic acid (FA), a high-affinity ligand for folate receptors, can be easily conjugated with other ligands, making it an excellent targeting agent. Folate receptors are highly expressed in various tumor cells (brain, breast, cervical, colon, epithelial, kidney, lung) and over 90% of ovarian cancer cells, with minimal expression in normal tissues. Their non-toxicity, stability, and ease of conjugation and characterization make them a popular target for drug development in ovarian cancer and other tumors.
Tongyi Pharmaceutical's three clinical-stage products are all small-molecule FRα bispecific ligand conjugates.
CBP-1008 targets folate receptor α (FRα) and transient receptor potential vanilloid 6 (TRPV6) with MMAE as the toxin, representing Tongyi Pharmaceutical's first Bi-XDC product. It has now received NMPA approval for the Phase III registration trial in platinum-resistant ovarian cancer (PROC).
CBP-1018 targets FRα and PSMA with MMAE as the toxin. Preliminary efficacy has been observed in mCRPC (metastatic castration-resistant prostate cancer) patients, further validating the Bi-XDC platform. Data presented by Tongyi Pharmaceutical at the 2024 ASCO showed that in the 0.14mg/kg and higher dose groups, 52% of patients experienced a decrease in PSA levels after single-agent CBP-1018 treatment. Among 9 patients with measurable lesions, the objective response rate (ORR) and disease control rate (DCR) reached 33.3% (3/9) and 100% (9/9), respectively. The median radiographic progression-free survival (rPFS) in all evaluable mCRPC patients was 9.2 months. CBP-1018 also demonstrated good tolerability, with no maximum tolerated dose (MTD) reached. Currently, the FDA has approved an I/II clinical trial application for CBP-1018 in combination with a novel endocrine therapy (enzalutamide).
CBP-1019 is a next-generation bispecific ligand conjugate targeting FRα and TRPV6, with a topoisomerase I inhibitor (TOPOIi) payload: the camptothecin derivative DX-8951. It has received orphan drug designations from the U.S. FDA for three indications (pancreatic cancer, esophageal cancer, and small cell lung cancer) and a fast-track designation for recurrent endometrial cancer (EC) in patients who have received at least one prior line of systemic platinum-based chemotherapy.
Preliminary Phase I/II clinical data showed that among 10 patients with advanced/metastatic EC treated with CBP-1019 at 3.0 mg/kg or 4.0 mg/kg, CBP-1019 exhibited excellent efficacy regardless of FRα/TRPV6 expression status. At the 3.0 mg/kg dose level (potential recommended Phase II dose, RP2D), 7 out of 9 patients with advanced/metastatic EC had at least one post-treatment tumor assessment, achieving an ORR of 42.9% and a DCR of 100%. CBP-1019 also showed good safety and tolerability, with no observed typical ADC-related adverse events associated with TOPOIi payloads, such as interstitial lung disease (ILD), stomatitis, or ocular toxicity.
Notably, the Bi-XDC platform can theoretically deliver various payloads, including small-molecule toxins, PROTACs, radioisotopes, photodynamic therapy agents, immunomodulators, NK cells, and T cells. Currently, Coherent Biopharma has laid out cutting-edge directions such as PROTAC Bi-XDC and radioligand Bi-XDC, extending the bispecific targeting technology to broader therapeutic fields. However, these therapies are still in the preclinical stage, and their safety and efficacy remain to be verified.
Recently, Tongyi Pharmaceutical's first bispecific small molecule drug conjugate, CBP-1008 (Rico-V), received approval from China's NMPA to initiate a Phase III clinical trial for platinum-resistant ovarian cancer (PROC).
As reported, this fully chemically synthesized bispecific ligand conjugate (Bi-XDC) has a molecular weight approximately 1/50 that of traditional ADC drugs, offering unique advantages in CMC (Chemistry, Manufacturing, and Controls) and treatment costs. The approval of Rico-V for the Phase III registration trial marks a significant step toward becoming the world's first Bi-XDC drug, promising a new therapeutic option for ovarian cancer patients.
Novel Therapy Overcomes the "King of Gynecological Cancers"
Ovarian cancer ranks first in mortality among gynecological malignancies, earning it the title of the "king of gynecological cancers." Often called the "silent killer" due to its lack of specific early symptoms, it is frequently diagnosed at an advanced stage.
According to 2024 statistics from China's National Cancer Center, there are approximately 61,100 new ovarian cancer cases and 32,600 deaths annually in China, with about 70% of patients diagnosed at an advanced stage. Current standard treatments include surgery combined with platinum-based chemotherapy ± targeted maintenance therapy, but most patients relapse and develop platinum resistance. Platinum-resistant ovarian cancer (PROC) has a poor prognosis and extremely limited treatment options.
While some innovative drugs have been approved recently-such as AbbVie's FRα ADC drug ELAHERE® (sacituzumab govitecan-hziy)-the unmet treatment needs of PROC patients remain substantial.
CBP-1008 brings hope to this dilemma. Developed based on Tongyi Pharmaceutical's proprietary Bi-XDC platform, it is the world's first bispecific ligand conjugate, simultaneously targeting FRα and TRPV6 receptors expressed on tumor cell membranes.
Clinical data released by Tongyi Pharmaceutical shows significant efficacy of CBP-1008 in PROC patients who received 1-3 prior lines of treatment. The median overall survival (mOS) reached 19.4 months (N=163), surpassing historical data for single-agent chemotherapy (≤3 lines of PROC) at 10.9-13.9 months and sacituzumab govitecan-hziy at 15.6-16.5 months.Notably, it remains effective in patients with low folate receptor expression, independent of folate expression levels.
In terms of safety, most adverse events (AEs) are mild to moderate. Unlike other antibody-drug conjugates (ADCs) using monomethyl auristatin E (MMAE) as the payload, Rico-V shows no significant ocular toxicity or peripheral neurotoxicity, which are common with such ADCs.
In production and supply, Rico-V, as a fully chemically synthesized small bispecific conjugate, has a molecular weight about 1/50 that of traditional ADCs. Its advantages in CMC-including simple synthesis/preparation, defined chemical structure, and easy control of production processes and quality indicators-result in significantly lower production and treatment costs compared to ADC drugs.
The NMPA's approval of CBP-1008 for the Phase III registration trial in PROC represents a crucial step toward clinical application, potentially providing a new treatment approach for platinum-resistant ovarian cancer patients.
Bi-XDC: The Next-Generation Conjugate Star
Traditional targeted chemotherapy drugs in clinical oncology suffer from low targeting, high side effects, easy development of drug resistance, and high recurrence rates. ADCs (Antibody-Drug Conjugates) combine traditional chemotherapy drugs with recombinant monoclonal antibodies via linkers, endowing chemotherapy drugs with active targeting capabilities for precise cancer treatment.
However, ADCs, as large-molecule biologics, face challenges such as complex production processes, high treatment costs, and suboptimal clinical safety.
Tongyi Pharmaceutical has developed a novel technology-bispecific ligand conjugates (Bi-XDC)-pioneering a new path in drug development.
A Bi-XDC molecule consists of four components: Ligand A targeting Receptor 1, Ligand B targeting Receptor 2, a therapeutic payload, and a linker. Through the synergistic interaction of two ligands with surface receptors on target tumor cells, Bi-XDC precisely delivers the conjugated payload to specific cells.
Compared to traditional ADCs, Bi-XDC drugs offer advantages such as broader target coverage, lower toxicity, and lower costs (enabling full chemical synthesis). On one hand, the pairing of bispecific ligands enhances target specificity and affinity, transforming two undruggable single targets into a druggable bispecific pair, thus enabling targeting of more previously undruggable targets. On the other hand, Bi-XDC maintains a relatively small molecular weight (about 1/50 that of ADCs), allowing faster cellular uptake and clearance from non-lesional tissues, significantly improving efficacy and safety.
Currently, Tongyi Pharmaceutical has three Bi-XDC products in clinical stages: CBP-1008, CBP-1018, and CBP-1019, covering high-need areas such as ovarian cancer, prostate cancer, and endometrial cancer.
Small molecules (e.g., folic acid, biotin, lactic acid, glycyrrhetinic acid) are easily accessible, cost-effective, low-toxic, free of immune stress, and readily characterizable and modifiable, making them widely used as targeting moieties in active targeted therapy for anticancer drugs.
Folic acid (FA), a high-affinity ligand for folate receptors, can be easily conjugated with other ligands, making it an excellent targeting agent. Folate receptors are highly expressed in various tumor cells (brain, breast, cervical, colon, epithelial, kidney, lung) and over 90% of ovarian cancer cells, with minimal expression in normal tissues. Their non-toxicity, stability, and ease of conjugation and characterization make them a popular target for drug development in ovarian cancer and other tumors.
Tongyi Pharmaceutical's three clinical-stage products are all small-molecule FRα bispecific ligand conjugates.
CBP-1008 targets folate receptor α (FRα) and transient receptor potential vanilloid 6 (TRPV6) with MMAE as the toxin, representing Tongyi Pharmaceutical's first Bi-XDC product. It has now received NMPA approval for the Phase III registration trial in platinum-resistant ovarian cancer (PROC).
CBP-1018 targets FRα and PSMA with MMAE as the toxin. Preliminary efficacy has been observed in mCRPC (metastatic castration-resistant prostate cancer) patients, further validating the Bi-XDC platform. Data presented by Tongyi Pharmaceutical at the 2024 ASCO showed that in the 0.14mg/kg and higher dose groups, 52% of patients experienced a decrease in PSA levels after single-agent CBP-1018 treatment. Among 9 patients with measurable lesions, the objective response rate (ORR) and disease control rate (DCR) reached 33.3% (3/9) and 100% (9/9), respectively. The median radiographic progression-free survival (rPFS) in all evaluable mCRPC patients was 9.2 months. CBP-1018 also demonstrated good tolerability, with no maximum tolerated dose (MTD) reached. Currently, the FDA has approved an I/II clinical trial application for CBP-1018 in combination with a novel endocrine therapy (enzalutamide).
CBP-1019 is a next-generation bispecific ligand conjugate targeting FRα and TRPV6, with a topoisomerase I inhibitor (TOPOIi) payload: the camptothecin derivative DX-8951. It has received orphan drug designations from the U.S. FDA for three indications (pancreatic cancer, esophageal cancer, and small cell lung cancer) and a fast-track designation for recurrent endometrial cancer (EC) in patients who have received at least one prior line of systemic platinum-based chemotherapy.
Preliminary Phase I/II clinical data showed that among 10 patients with advanced/metastatic EC treated with CBP-1019 at 3.0 mg/kg or 4.0 mg/kg, CBP-1019 exhibited excellent efficacy regardless of FRα/TRPV6 expression status. At the 3.0 mg/kg dose level (potential recommended Phase II dose, RP2D), 7 out of 9 patients with advanced/metastatic EC had at least one post-treatment tumor assessment, achieving an ORR of 42.9% and a DCR of 100%. CBP-1019 also showed good safety and tolerability, with no observed typical ADC-related adverse events associated with TOPOIi payloads, such as interstitial lung disease (ILD), stomatitis, or ocular toxicity.
Notably, the Bi-XDC platform can theoretically deliver various payloads, including small-molecule toxins, PROTACs, radioisotopes, photodynamic therapy agents, immunomodulators, NK cells, and T cells. Currently, Coherent Biopharma has laid out cutting-edge directions such as PROTAC Bi-XDC and radioligand Bi-XDC, extending the bispecific targeting technology to broader therapeutic fields. However, these therapies are still in the preclinical stage, and their safety and efficacy remain to be verified.
Conclusion
Tongyi Pharmaceutical has pioneered the Bi-XDC technology platform, with its first new drug, CBP-1008, approved for Phase III clinical trials. However, first-in-class innovative drugs carry both risks and opportunities; every step in bringing a new mechanism drug to market faces the risk of failure. If CBP-1008 succeeds in Phase III, it will provide a breakthrough treatment option for platinum-resistant ovarian cancer patients, establishing Tongyi Pharmaceutical as a leader in this field.
Reference sources:
1. https://mp.weixin.qq.com/s/nLWLgf_lAOMF29CxBKEscw
2. https://mp.weixin.qq.com/s/xyc8udeEw5lFSQ29Z1w_fw
2. https://mp.weixin.qq.com/s/xyc8udeEw5lFSQ29Z1w_fw
3. https://mp.weixin.qq.com/s/QW6L3dldEUFjqvQYG9l_RA