Corbus Pharmaceuticals, a precision oncology company, today announced that it has entered into an exclusive licensing agreement with CSPC Megalith Biopharmaceutical, a subsidiary of Hong Kong-based CSPC Pharmaceutical Group for development and commercialization of CRB-701 (SYS6002), a novel clinical stage antibody-drug conjugate (ADC) designed for improved therapeutic index and to act on a broad range of Nectin-4 expressing tumors.

Nectin-4, a poliovirus receptor-related-4 (pvrl-4) encoded protein, is a Ca2+ independent immunoglobulin-like protein. Along with other Nectins (Nectin-1, -2 and -3), it is primarily involved in cell-cell adhesion. [1]

Nectin‑4 is particularly overexpressed in breast, lung, urothelial, colorectal, pancreatic and ovarian cancer. Furthermore, the upregulation of Nectin‑4 is an independent biomarker for overall survival. [2]

The agreement between Corbus and CSPS covers exclusive commercialization rights to CRB-701 in the United States, Canada, the European Union (including the European Free Trade Area), the United Kingdom, and Australia. CSPC will retain all rights to SYS6002 in the remaining global markets.

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Site specific
Utilizing the CSPC proprietary enzyme-catalyzed site-specific antibody conjugation technology, the CRB-701 (SYS6002) direct the potent mitotic inhibitor MMAE specifically to Nectin-4 expressing cancer cells. The stability of the linker can also facilitate the delivery of high concentration of MMAE into the tumor and reduce side effects with the decrease in undesirable systemic exposure.

Site specific conjugation and novel linker technology enables homogenous payload incorporation and release with high plasma stability and low free plasma payload.

Single enzyme, KLICK™ linker chemistry with modification of a native antibody with a simpler and cheaper CMC.

CRB-701 offers a differentiated by immune-mediated tumor destruction functionality. The CRB-701 antibody has built-in Fc receptor binding activity, leading to innate immune mediated tumor destruction.

In preclinical studies, CRB-701 has demonstrated potency against FcγR1, C1q and FcRn. This additional antibody functionality is designed to increase efficacy of CRB-701 via a secondary mechanism

Promising therapeutic target
Nectin-4 promotes tumor proliferation, angiogenesis, lymphangiogenesis and lymphatic metastasis, and its expression is at a very low level in healthy adult human tissues. However, in many types of cancer including bladder, triple negative breast, lung, colorectal, pancreatic and ovarian cancers, high-level expression of Nectin-4 is reactivated. The upregulation of Nectin-4 is also an independent biomarker for poor overall survival in several types of cancer.

Due to its selective expression in cancer, Nectin-4 has become a promising therapeutic target for various cancers. The Product was designed to have homogeneous DAR distribution, better stability of the proprietary linker and reduced drug to antibody ratio in order to improve blood stability and tumor-specific drug release for better safety profile and efficacy.

The IND for CRB-701 has been cleared by the United State Food and Drug Administration (FDA).

Clinical development
The investigational agent is currently being studies  by CSPC in a Phase 1 dose escalation clinical trial in advanced solid tumors in China, focusing on urothelial cancer and other Nectin-4-positive solid tumors potentially including lung, breast and prostate cancer.

Corbus is planning to bridge data from this Phase 1 trial to support a US clinical trial starting in 2024. Corbus and CSPC will work collaboratively to execute the clinical development of CRB-701 with Corbus responsible for the clinical development in the US and other licensed territories.

“This agreement adds a promising clinical-stage asset with a validated mechanism of action to our pipeline and reinforces the evolution of Corbus into a precision oncology company. We will leverage the R&D infrastructure that we have established for our TGFβ modulator (CRB-601) to also enhance our understanding of Nectin-4,” noted Yuval Cohen, Ph.D., Chief Executive Officer of Corbus.

“By combining recent cost-reduction measures as well as prioritization of resources to this new program, we can maintain our previously stated cash runway through the second quarter of 2024.”

CSPC will receive an upfront payment of US $ 7.5 million. CSPC will also be eligible to receive royalties on net sales and up to US $ 130 million in potential development and regulatory milestone payments and US $ 555 million in potential commercial milestone payments.

“CRB-701 has several key features that support a differentiated profile,” said Rachael Brake, Ph.D., Chief Scientific Officer of Corbus.

“These include site specific conjugation chemistry that leads to low payload release in plasma, a novel Fc-enabled antibody with an improved pharmacokinetic profile and toxicology data that suggests that there is an ability to achieve higher exposures with CRB-701. We look forward to working with CSPC to advance clinical development of this asset and realize its full potential.”

“This partnership with Corbus, is an example of our focused effort to bring our innovative pipeline overseas to help patients battling cancer. We look forward to collaborating with Corbus with the goal of developing this ADC as a potentially impactful treatment option to patients in need,” said Zhang Cuilong, Chief Executive Officer of CSPC.

Today, enfortumab vedotin (Padcev®; Seagen/Astellas) is the only FDA-approved Nectin-4 targeting ADC for the treatment of in urothelial cancer.

Highlights of prescribing information
Enfortumab vedotin (Padcev®; Seagen/Astellas)[Prescribing Information]

[1] Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol. 2021 Nov 15;911:174516. doi: 10.1016/j.ejphar.2021.174516. Epub 2021 Sep 20. PMID: 34547246.
[2] Liu Y, Han X, Li L, Zhang Y, Huang X, Li G, Xu C, Yin M, Zhou P, Shi F, Liu X, Zhang Y, Wang G. Role of Nectin‑4 protein in cancer (Review). Int J Oncol. 2021 Nov;59(5):93. doi: 10.3892/ijo.2021.5273. Epub 2021 Oct 19. PMID: 34664682.

Featured image: Honk Kong skyline. Photo by Daniam Chou on Unsplash. Used with permission.

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