Leading the Development of Bispecific ADCs, Multiple Chinese New Drugs Go Global

On November 18, it was announced that VelaVigo has entered into a global strategic cooperation agreement with Avenzo Therapeutics. According to the agreement, Avenzo Therapeutics will obtain the rights to develop, produce, and commercialize VelaVigo's Nectin4/TROP2-targeted bispecific antibody-drug conjugate (ADC) worldwide, excluding Greater China. VelaVigo will receive an upfront payment of up to USD 50 million and recent milestone payments, with up to USD 750 million in subsequent milestone payments upon achieving key milestones in development, regulatory approval, and sales, as well as tiered royalties based on sales in the licensed territories.

VelaVigo is a biotechnology company engaged in the discovery and development of multispecific antibodies and ADCs. Since founded in 2021, it has established extensive R&D pipelines covering more than ten first-in-class/best multispecific antibodies and ADC molecules, which focus on fields such as oncology and autoimmune diseases. In addition, with the aim of enhancing global clinical development and collaboration, VelaVigo has also established VelaVigo Bio in the United States.

This collaboration represents a crucial part of VelaVigo's globalization strategy, which also puts bispecific ADCs in the spotlight. Incomplete statistics shows that multiple bispecific ADCs from China have gone global before this:

• In December 2023, SystImmune, a wholly-owned subsidiary of Biokin Pharmaceutical in the United States, and Bristol Myers Squibb (BMS) reached an exclusive licensing and cooperation agreement for BL-B01D1, a bispecific ADC targeting EGFR/HER3 developed by Biokin Pharmaceutical. According to the agreement, BMS will pay Biokin Pharmaceutical an upfront payment of USD 800 million and up to USD 500 million in recent contingent payments. Biokin Pharmaceutical is eligible to receive up to USD 7.1 billion in additional payments upon achieving development, regulatory, and sales performance milestones, with a potential total consideration of up to USD 8.4 billion.

• In January 2024, Biocytogen entered into an exclusive option and licensing agreement with Radiance. The agreement grants Radiance an option to license from Biocytogen a first-in-class fully human HER2/TROP2 bispecific ADC for development, manufacturing and commercialization worldwide.

• In August 2024, Kelun Pharmaceutical announced that MSD will exercise the exclusive option on Kelun Biotech's bispecific ADC project SKB571 and will pay Kelun Pharmaceutical USD 37.5 million, with further milestone payments to be made upon achieving specific development and sales milestones.

• In November 2024, Biocytogen announced that IDEAYA Biosciences has exercised its option to obtain the global exclusive license for Biocytogen's B7H3/PTK7-targeted bispecific ADC project IDE034. In accordance with the agreement, Biocytogen will receive upfront payment and option exercise fees, development and regulatory milestone payments, commercialization milestone payments and a share of net sales volume, with a total of USD 406.5 million.

In addition, in April 2024, Genmab acquired ProfoundBio for USD 1.8 billion, acquiring multiple drugs, including the EGFR/cMET-targeted bispecific ADC PRO1286. In September 2024, CSPC Pharmaceutical Group Co., Ltd and Alphamab Oncology also reached a licensing agreement totaling up to RMB 3.08 billion for the latter's HER2-targeted bispecific ADC JSKN003.

The frequent collaborations among enterprises indicate the promising market prospects of bispecific ADCs from the side. The overseas expansion of bispecific ADCs made in China demonstrates that the R&D capabilities of Chinese pharmaceutical companies are gradually being recognized by foreign enterprises, and their strength in the field of bispecific ADCs should not be underestimated.

ADC and bispecific antibodies are both popular areas in drug R&D and have gained tremendous success. Bispecific ADCs, obtained by bispecific antibodies (BsAbs) with cytotoxins through linker chains, integrate the advantages of ADCs and BsAbs, representing a hot direction for future new drug R&D. Currently, bispecific ADCs under development can be divided into two major categories: dual-target ADCs (targeting two different epitopes) and dual-epitope ADCs (targeting different epitopes of the same target).

As for R&D progress, Biokin Pharmaceutical's BL-B01D1, Alphamab Oncology's JSKN003, and Chiatai Tianqing's TQB2102 have made relatively rapid progress, all of which have entered Phase II clinical research. Among them, BL-B01D1 is the world's first-in-class EGFR/HER3-targeted bispecific ADC, composed of SystImmune's proprietary bispecific antibody and a payload containing a stable, cleavable linker and a topoisomerase inhibitor. Currently, BL-B01D1 is under Phase III clinical research in a variety of tumors, such as EGFR-mutated and wild-type NSCLC, nasopharyngeal carcinoma, esophageal squamous cell carcinoma, triple negative breast cancer, and HER2-HR + breast cancer.

In April 2024, BL-B01D1 was included in the Breakthrough Therapy Designation by Center for Drug Evaluation for recurrent or metastatic nasopharyngeal carcinoma patients who have previously been treated with PD-1/PD-L1 monoclonal antibodies and at least two lines of chemotherapy (at least one line containing platinum) and failed.

According to results from the first-in-human, open-label, multicenter Phase I clinical research of BL-B01D1 for the treatment of locally advanced or metastatic solid tumors, published in Lancet Oncol in May 2024: BL-BO1D1 demonstrated good safety and antitumor activity. Moreover, the drug exhibited encouraging antitumor activity in previously treated patients with solid tumors.

JSKN003 is a novel ADC targeting two epitopes of HER2, self-developed by Alphamab Oncology utilizing its proprietary glycosylation site-specific conjugation platform. In accordance with the preclinical research: Compared with drugs of the same kind, JSKN003 has better serum stability, stronger bystander killing effect and equivalent tumor-killing activity, effectively expanding the therapeutic window. Currently, Phase III clinical research of JSKN003 for HER2 low-expressing breast cancer has commenced.

The Phase I clinical research results of JSKN003 in Australia for the treatment of HER2-expressing advanced solid tumors, presented at AACR Annual Meeting 2024, demonstrated that JSKN003 showed excellent tolerability and safety in patients with advanced/metastatic solid tumors who had previously received multiple lines of systemic therapy, and showed encouraging preliminary antitumor activity. The incidence of hematological toxicity and interstitial lung disease (ILD) was low. As of the data cutoff date, all patients had completed the dose-limiting toxicity (DLT) observation period, with no DLT events occurring, and the MTD had not been reached.

TQB2102 is a bispecific ADC targeting two non-overlapping epitopes, ECD2 and ECD4, of HER2. Compared with monoclonal antibodies and monoclonal antibody ADCs, TQB2102 has stronger binding, internalization efficiency and killing effects on tumor cells, and shows advantages for tumors with low expression of HER2. Currently, Phase III clinical research of TQB2102 in the treatment of recurrent/metastatic breast cancer with low HER2 expression is underway.

Innovent's IBI3001, DualityBio's DB-1419, and ProfoundBio's PRO1286 have also entered the clinical trial stage. Among them, IBI3001 is an EGFR/B7H3-targeted bispecific ADC. In accordance with the preclinical research announced at AACR Annual Meeting 2024: The drug exhibited potent tumor-killing effects in both in vitro and in vivo models of multiple solid tumors, with high tolerability and a therapeutic window of up to 40 times. At present, IBI3001 is undergoing a Phase I/II multicenter, open-label clinical research abroad.

DB-1419 is a potential first-in-class bispecific ADC targeting B7-H3/PD-L1, utilizing a novel binding and endocytosis mechanism to demonstrate superior efficacy compared with traditional monoclonal antibody ADCs and effectively overcome resistance issues caused by decreased single-target expression. In accordance with the preclinical research: DB-1419 can kill cancer cells and activate T cells, exhibiting stronger tumor growth inhibitory activity than a monospecific B7-H3 ADC in immune reconstitution models. In September 2024, Phase I/IIa first-in-human research of DB-1419 for the treatment of advanced/metastatic solid tumors received approval from FDA and TGA, and the first patient was dosed

PRO1286 is a bispecific ADC targeting EGFR/cMET, meticulously designed using ProfoundBio's proprietary platform, suitable for many tumors expressing EGFR and cMET, regardless of the presence of targeted genomic alterations (AGA). In accordance with the preclinical research: PRO1286 shows excellent physicochemical properties, PK/PD, antitumor activity, and tolerability. In September 2024, PRO1286 was approved for clinical trials in China for the treatment of solid tumors.

Moreover, there are multiple bispecific ADCs in preclinical stages in China, such as YH012, YH013, BCG011, BCG012, and BCG013 from Biocytogen, JY108, JY207, and JY201 from Enduring, VBC101-F11 and VBC103 from VelaVigo, and DXC024 and DXC025 from DAC Biotechnology.

Overall, bispecific ADCs exhibit diversity in target sites, linker technologies, and cytotoxins. In addition, Chinese pharmaceutical companies have excelled in the field of bispecific ADCs, with rapid progress in drug R&D. It is expected that bispecific ADCs, with the relentless efforts of pharmaceutical companies, will soon achieve significant breakthroughs, benefiting tumor patients.

About the author

Yi

a pharmacist pays attention to the research and development trends of new drugs at home and abroad, expects to improve himself in the continuous input and output, and grow together with medical we-media.