BMS Terminates $1.56 Billion TIGIT Bispecific Antibody Collaboration with Agenus

On August 5, there were new developments disclosed in three major bispecific antibody project collaborations. Two brought concerns, and one brought joy.

 

First, BMS (Bristol-Myers Squibb) announced the termination of the deal for the TIGIT bispecific antibody with Agenus (NASDAQ: AGEN), a cancer immunotherapy company. Just three years ago, BMS had acquired the project for $200 million. BMS informed Agenus of this decision last week.

 

And on May 18, 2021, BMS announced a $1.56 billion licensing agreement with Agenus (including a $200 million upfront payment and $1.36 billion in milestone payments) to obtain the global exclusive rights to Agenus' proprietary bispecific antibody program AGEN1777. AGEN1777 is a first-in-class bispecific anti-TIGIT antibody targeting TIGIT and another major inhibitory receptor expressed on T cells and NK cells to enhance anti-tumor activity.

 

Later in the same year, when the first patient was enrolled in the Phase I clinical trial of AGEN1777, BMS immediately paid $20 million and awarded Agenus a $25 million milestone payment for the Phase 2 study that began in January 2024. However, BMS has now decided not to include AGEN1777 in its development plan.

 

BMS's Termination of Cooperation Negatively Impacts Agenus: Its Stock Price Fell About 4% in Pre-Market Trading to Below $5.4.

The Complex Mechanism of Action of the TIGIT Target Bends Giants

Agenus, Inc. was founded in 1994, with its headquarters in Lexington, Massachusetts, USA. At that time, it was named Antigenics Inc., co-founded by Garo H. Armen and Pramod K. Srivastava. In 2000 and 2001, Antigenics successively acquired Aquila Biopharmaceuticals and Aronex Pharmaceuticals to expand its own pipeline and successfully went public on NASDAQ.

 

In January 2011, Antigenics officially changed its name to the current Agenus. Subsequently, it embarked on its business development (BD) journey. In March 2012, GlaxoSmithKline paid $9 million in patent fees for Agenus' QS-21 Stimulon® adjuvant; In 2014, after acquiring the European biotechnology company 4-Antibody, Agenus caught the attention of Merck, with whom it reached a $100 million agreement. Merck will utilize Agenus' Retrocyte Display platform technology to develop antibodies targeting an undisclosed pair of cancer treatment checkpoint targets.

 

Currently, Agenus owns the Retrocyte Display expression platform, which is used for identifying fully humanized and humanized monoclonal antibodies, and has developed a pipeline around it. The research projects include heat shock protein vaccines and various monoclonal antibody drugs. Among them, Agenus has established two pipelines targeting TIGIT—AGEN1327, a monospecific anti-TIGIT antibody; and the recent highlight, AGEN1777, a bispecific anti-TIGIT antibody.

 

In fact, TIGIT itself has been constantly embroiled in controversy.

 

TIGIT, namely T-cell immunoglobulin and ITIM domain protein, is specifically expressed on NK cells and T cells. It interacts with PVR (CD155) and PVR-like proteins PVRL2 and PVRL3 (with higher affinity for PVR and PVRL3, and lower affinity for PVRL2). CD96 and CD226 compete with TIGIT in binding to PVR.

 

In 2002, the Genentech research team first discovered this gene specifically expressed in T cells and NK cells; in 2009, TIGIT appeared for the first time in Nature Immunology. The article confirmed that TIGIT has an immunoglobulin-like (IgV) domain and an immunoreceptor tyrosine-based inhibitory motif (ITIM). Therefore, scientists named this protein TIGIT (T-cell immunoreceptor with Ig and ITIM domains), which plays an important role in suppressing T cells and NK cells.

 

Subsequent research found that TIGIT, a member of the Poliovirus Receptor (PVR)/Nectin family, is a co-inhibitory receptor expressed in lymphocytes. On T cells, TIGIT modulates T-cell activity (inhibitory effect) through its interaction with PVR on the surface of dendritic cells. This modulation is achieved by PVR controlling the secretion of cytokines from dendritic cells (changes in the secretion levels of these cytokines affect T-cell activity). On natural killer (NK) cells, TIGIT inhibits the cytotoxic effects of NK cells via interactions with PVR and PVRL2. This regulation occurs directly through the intracellular ITIM motif of TIGIT modulating its downstream signaling pathways.

 

It is worth mentioning that, unlike most known immune checkpoints and their ligands, which generally have a one-to-one or one-to-many relationship, TIGIT maintains a "many-to-many" relationship with ligands CD226, CD96, CD112, and CD155. This has led to the medical community not yet fully understanding the mechanism of TIGIT, which is also one of the main reasons for the difficulty in TIGIT research and development.

 

However, the difficulty has not affected the fierce competition landscape; it's just that the market is still waiting for a winner to emerge.

 

After PD-(L)1, TIGIT was once considered one of the most promising and potential targets, but its development process has not been smooth. Taking Roche, the leader in TIGIT research and development, as an example, in 2020, Roche announced the Phase Ia clinical trial of its TIGIT antibody Tiragolumab for the monotherapy treatment of non-small cell lung cancer. The results showed that the total response rate of 24 patients treated with Tiragolumab monotherapy was 0. Roche did not give up, but in 2022, the Phase III clinical SKYSCRAPER-02 study results of Tiragolumab showed that Tiragolumab+Tecentriq+chemotherapy failed to reach the co-primary endpoint of PFS compared with the control group chemotherapy, and did not reach the co-primary endpoint of overall survival (OS) in subsequent interim analyses.

 

BMS announced its decision to terminate the Phase II clinical trial of its anti-TIGIT drug BMS-986207 when releasing its 2022 financial results. Dr. Samit Hirawat, Chief Medical Officer of BMS, stated that toxicity of BMS-986207 was observed during combination immunotherapy, and the company decided to terminate this trial for safety reasons. This is another setback in the TIGIT research and development field following Roche. According to incomplete statistics from Cytiva, there are currently more than 80 TIGIT drugs under development, nearly half of which are in the preclinical research stage.

 

Back to the entanglement between BMS and Agenus. BMS’s engagement with Agenus can be described as a “four-part series”: betting on TIGIT monoclonal antibody, abandoning TIGIT monoclonal antibody, shifting to TIGIT bispecific antibody, and then abandoning TIGIT bispecific antibody. According to Agenus, BMS is returning the rights to the bispecific antibody and stated: "This is part of a broader strategic adjustment involving the development pipeline of other licensed products."

Giants Successively Exit Bispecific Antibody Projects

Not coincidentally.

 

On the same day, Genmab, a company focused on developing innovative and differentiated antibody therapies, announced that BioNTech had chosen not to participate further in the development of the PDL1/4-1BB bispecific antibody acasunlimab project. Genmab will take full responsibility for the ongoing development and potential commercialization of acasunlimab. The project will depend on certain milestone payments from Genmab to BioNTech as well as single-digit tiered royalties on net sales. Genmab plans to initiate Phase III studies in the second half of this year.

 

Among them, Acasunlimab is an investigational PD-L1/4-1BB bispecific antibody that combines Genmab's proprietary DuoBody technology platform with BioNTech's proprietary immune-modulatory antibody. Acasunlimab aims to induce an anti-tumor response by conditionally activating 4-1BB on T cells and natural killer (NK) cells, which strictly depends on the simultaneous binding of the PD-L1 arm. At the 2024 ASCO conference, Phase II data on Acasunlimab for the treatment of previously treated PD-L1+ (TPS≥1%) non-small cell lung cancer (NSCLC) was disclosed (NCT05117242). The unconfirmed ORR in the Acasunlimab monotherapy cohort was 31%, with a confirmed ORR of 13%.

 

The high R&D difficulty and unsatisfactory clinical outcomes of TIGIT drugs, among other reasons, make it understandable for many giants to withdraw, although BMS cited strategic adjustment as the reason. Coincidentally, BioNTech's decision to exit was also based on considerations of its product portfolio strategy. BioNTech stated that its long-term partnership with Genmab in the field of antibody science remains intact, and both parties will continue to develop existing projects under the existing agreement, which was expanded in 2022.

On the same day, on the other side, China-produced bispecific antibodies go global

On the same day, August 5, 2024, Genor Biopharma issued an announcement stating that the Group had entered into a licensing agreement and equity agreement with TRC 2004 (a company co-founded by Two River, Third Rock Ventures, and Genor Biopharma in Delaware, USA). According to the licensing agreement, Genor Biopharma has agreed (among other things) to grant the licensee global rights outside of Greater China to develop, use, manufacture, commercialize, and otherwise exploit the CD3/CD20 bispecific antibody GB261.

 

According to the terms of the license agreement and equity agreement, Genor Biopharma will receive a substantial equity stake in TRC 2004, tens of millions of dollars in upfront payments, $443 million in milestone payments, and single-digit to double-digit percentage royalties on sales. Additionally, Genor Biopharma's overseas expansion will be carried out under the NewCo model.

 

The pipeline GB261 involved is a bispecific antibody targeting CD20 and CD3 designed by AB Studio's high-low dual resistance platform and further developed by Genor Biopharma, which is a novel differentiated CD20/CD3 bispecific T-cell engager (TCE) with ultra-low CD3 binding affinity and complete Fc function (ADCC and CDC).

 

As early as August 31, 2021, Genor Biopharma announced that the first patient with B-cell non-Hodgkin lymphoma (B-NHL) had been enrolled in the first-in-human (FIH) clinical trial of its GB261, conducted at the Peninsula & South Eastern Haematology & Oncology Group center in Australia. This clinical trial for the CD20/CD3 bispecific antibody targeting treatment of B-cell non-Hodgkin lymphoma (B-NHL) was previously submitted by Australia's Bellberry Human Research Ethics Committee (Bellberry HREC). Thus, GB261, as an innovative bispecific T Cell Engager globally, completed the submission, review by the Australian ethics committee, and enrollment of the first patient in its first-in-human study, rapidly achieving the first entry into clinical trials for a China-produced CD3/CD20 bispecific antibody.

 

On the same day, three bispecific antibody projects met with completely different fates. However, GB261 from Genor Biopharma and acasunlimab from Genmab offered room for imagination regarding market prospects due to their differentiated advantages and promising clinical outcomes; in contrast, Agenus still has a way to go in conquering the challenging TIGIT target.

 

Subsequently, Agenus plans to further explore the development of the candidate drug, including considering its combination with other assets, and seeking new partners for AGEN1777.