revolutionizing cancer and autoimmune therapies

T cell engagers represent a novel approach to tuning the immune system to target and kill tumor cells, expanding treatment options for cancer. The first T cell engager drug earned regulatory approval in 2014, and since then, the field has been growing with major licensing deals beyond cancer and candidates forging through the clinic.

What are T cell engagers?

This class of drugs has shot to fame in recent years because of their ability to harness the immune system. T cell engagers are antibodies that are engineered to recognize and kill harmful cells, be it tumor cells in the case of cancer or autoreactive cells in the case of autoimmune diseases. They achieve this by binding to the cell antigen and a T cell receptor, bringing them close enough to induce T cell activation and targeted cell killing.

T cell engagers are designed to enhance immunotherapy. According to Mark Cobbold, head of Immuno-Oncology Discovery and Oncology Cell Therapy at AstraZeneca, in the case of cancer, although immune cells play an important role in eliminating abnormal cells, “immunity against the tumor is often absent in patients with cancer,” which is where T cell engagers can act as a bridge between T cells and cancer cells to more precisely target them.

T cell engagers: which ones have been approved?

Big pharmas have been in the T cell engager space for a good while now. In fact, pharma giant Amgen’s drug was the first of its kind to be approved by the U.S. Food and Drug Administration (FDA). Blinatumomab, known by its brand name Blincyto, is a bispecific CD19-directed CD3 T cell engager for lymphoblastic leukemia (ALL). Its approval back in 2014 was based on a phase 2 study where 41.6% of 185 patients achieved complete remission or complete remission with partial hematologic recovery – meaning that the blood counts may still be low – within two cycles of treatment with the drug, which was regarded as the primary endpoint of the study.

Several T cell engagers have been greenlit by the FDA in recent years. These include Janssen’s Tecvayli (teclistamab-cqyv), which was the first bispecific T cell engager to be cleared for treating patients with relapsed or refractory multiple myeloma, a cancer that forms in the plasma cells, in 2022. Following this, Pfizer’s Elrexfio (elranatamab) was granted approval a year later for the same indication. 

And last year, Amgen’s second T cell engager Imdelltra (tarlatamab-dlle) was cleared by the FDA to treat small cell lung cancer (SCLC), the first cell engager therapy to be authorized for the disease. SCLC is a difficult-to-treat disease, and less than 3% of patients with extensive-stage SCLC live longer than five years, so Imdelltra’s approval was a “watershed moment,” according to Paul Burton, chief medical officer (CMO) of Amgen, in an interview with Fierce Biotech last year.

Also calling it a “significant milestone for the SCLC community,” Laurie Fenton Ambrose, CEO of GO2 for Lung Cancer, said in a press release: “After decades of minimal advancements in the SCLC treatment landscape, there is now an effective and innovative treatment option available.”

Other T cell engagers that have been cleared to treat cancer include Genentech’s Columvi (glofitamab-gxbm) for relapsed or refractory diffuse large B-cell lymphoma – a blood cancer of the B cells – and Lunsumio (mosunetuzumab-axgb) for follicular lymphoma – a type of B-cell lymphoma – marking firsts in both indications.

Big pharmas engage in enhancing immunotherapies

As these big pharmas rack up approvals for their T cell engagers, it would come as no surprise that other pharma giants are trying to get their hands on preclinical and clinical candidates.

Most recently, British multinational pharmaceutical AstraZeneca revealed clinical data of AZD0486, a CD3xCD19 bispecific T cell engager, which it had acquired after it bought the biotech TeneoTwo in 2022. The phase 1 results showed significant progress in patients with follicular lymphoma and diffuse large B cell lymphoma treated with the drug. A 96% objective response rate was achieved in patients with follicular lymphoma, with 85% of them having a complete response. The results were presented at the American Society of Hematology’s annual summit in December.

Another milestone in the therapeutic sector in recent years is the FDA awarding Fast Track designation to Boehringer Ingelheim’s BI 764532 for SCLC in patients whose disease has progressed following at least two prior lines of treatment. This was after it called on U.K.-based Oxford BioTherapeutics to discover T cell engagers almost five years ago. The candidate is currently in a phase 2 study for patients with relapsed or refractory extensive-stage SCLC and other relapsed or refractory neuroendocrine carcinoma (NEC), a rare, highly aggressive cancer.

Aside from the growing number of clinical trials for T cell engagers in cancer care, this class of drugs has the scope to treat autoimmune diseases as well. Candid’s splurge on deals establishes this, but so do other collaborations like British multinational GSK’s $300 million purchase of China-based Chimagen Biosciences’ engager therapy. The candidate in question is CMG1A46, which has the potential to deplete uncontrolled B cells, a biomarker in autoimmune diseases such as lupus. GSK plans to push CMG1A46 to the clinic for lupus this year, and it is already undergoing phase 1 trials for certain blood cancers.

T cell engagers in the clinic: Janux, Molecular Partners, Crescendo, and Lava in early-stage trials

By 2030, these drugs are predicted to generate $20.6 billion, a more than 1,320% hike from 2023, according to GlobalData. And Tecvayli is poised to dominate global sales in the T cell engager space by then. But is there competition lurking?

At present, there are a number of T cell engagers in the clinic. California-based Janux Ther­a­peu­tics has two candidates in phase 1 trials. Its lead candidate JANX007 is designed to target PSMA, a protein expressed in prostate cancer tumors, and is being tested for the treatment of metastatic castration-resistant prostate cancer (MCRPC). Its other candidate JANX008 targets the epidermal growth factor receptor (EGFR) and is being evaluated to treat solid tumors.

The candidates were born out of Janux’s technology platform, which aims to overcome the safety and efficacy limitations of traditional T cell engagers, such as the overactivation of the immune system leading to CRS, on-target, off-target effects, and poor pharmacokinetics leading to a short half-life. So, it has employed its masking technology to engineer drug candidates called tumor activated T cell engagers (TRACTrs), which are designed to enhance tumor-specific activation. 

Meanwhile, British biotech Crescendo Biologics’ T cell engager also targets prostate cancer. The phase 1 candidate is a trispecific antibody that, like JANX007, targets PSMA. As Crescendo described it, the drug’s design enables the agonism of CD137 selectively in the presence of PSMA-positive tumor cells, enabling tumor-specific T cell activation whilst minimizing systemic activation.

Another candidate in phase 1 is Swiss biotech Molecular Partners’ T cell engager, which has also been designed to overcome CRS when treating acute myeloid leukemia (AML) – a highly resistant type of cancer with an urgent need for effective therapies. Nearly half of the patients with AML in the U.S. die within two years of their diagnosis because currently available treatments haven’t proven to entirely wipe out cancer cells. Moreover, T cell engagers have struggled to tackle AML without people experiencing CRS, which can be deadly.

So, MP0533 has been created to target the tumor-associated proteins CD33, CD123, and CD70, as AML cells commonly co-express at least two of the three target antigens. The higher the number of target antigens present, the improved likelihood of the drug binding to AML cells instead of healthy cells, thereby sparing the healthy cells from damage.  

Additionally, Dutch biotech Lava Therapeutics is also pushing its pipeline through the clinic, despite its former lead T cell engager LAVA-1207 being binned in December. It’s now focusing on its CD-123-targeted candidate LAVA-1266 for blood cancers and its Pfizer- and Johnson and Johnson-partnered cell engagers.

New technologies related to T cell engagers:

Candid Therapeutics on a T cell engagers partnership spree

As biotechs boost their T cell engager pipelines, many are looking for partnerships to do so. One biotech partaking in a series of licensing deals in the T cell engagers space since December is California-based Candid Therapeutics. It sealed a deal worth more than a billion dollars with Chinese company EpimAb Biotherapeutics to discover and develop T cell engagers to broaden its pipeline in December. At the same time, it signed partnerships with young American biotechs Nona Biosciences and Ab Studio to advance its position in the field to address autoimmune diseases. The deal with Nona will cost Candid up to $320 million in upfront and milestone payments.

And then, just last month, it began a collaboration with Chinese biotech WuXi Biologics for a preclinical trispecific T cell engager discovered by WuXi. Candid is set to pay up to $925 million in upfront and milestone payments for the candidate.

“To further solidify our leadership position in T cell engagers to deplete B cells for treatment of autoimmune and inflammatory diseases, this transaction uniquely positions us with three T cell engager programs targeting BCMA, CD20, and CD19 in or near clinical development,” said Dr. Ken Song, president and chief executive officer (CEO) of Candid, in a press release regarding the deal with WuXi.

T cell engagers attract biotech collaborations

Apart from Candid’s deals to both nab and discover T cell engagers, several other biotechs have made moves in the space. Late last year, Paris-based Ipsen and Biomunex joined forces to develop BMX-502, a bispecific antibody engaging MAIT cells – a type of T cell – to kill cancer cells. In exchange for up to $610 million, Ipsen has secured the global licensing rights to the drug, which is currently in the preclinical stage.

Plus, German company Medigene struck a three-year deal with WuXi Biologics to combine Medigene’s T cell receptor (TCR) generation expertise with the latter’s T cell engager platform to create off-the-shelf T cell engagers last year.

German biotechs Evotec and Glycotope also signed a pact in December 2023. Using Glycotope’s antibodies and Evotec’s immune cell engager platform, the two plan on developing new immune cell engagers. 

“The ability of Glycotope’s antibodies to target highly specific tumor-associated protein/carbohydrate combined glyco-epitopes (GlycoTargets) means that their combination with the Evotec platform has significant potential to develop next-generation immune cell engager bispecifics to address solid tumor indications,” said Cord Dohrmann, chief scientific officer of Evotec, in a press release.

Even big pharmas like AbbVie want in on the action. It tapped American startup EvolveImmune Therapeutics for an option-to-license T cell engagers based on EvolveImmune’s platform to address solid tumors and blood cancers in October. AbbVie spent $65 million upfront and can pay up to $1.4 billion to EvolveImmune for its candidates.

T cell engagers vs. CAR-T

As more and more buyouts take place in the field, what makes this class of drugs so in demand? 

According to a research paper published in Blood Advances by the American Society of Hematology, T cell engagers may be a better treatment option compared to CAR-T therapy for patients with blood cancers. CAR T cells can persist and expand in patients and are typically given as a single transfusion, whereas T cell engagers require continuous intravenous infusion.

“The great advantage of this approach is an increase in the safety profile, as the infusion can be stopped at any time, thereby reversing immune activation and immune-related adverse events,” the paper stated.

So, even though both kinds of therapy can lead to side effects such as cytokine release syndrome (CRS) and neurotoxicities, the general safety profile of T cell engagers trumps that of CAR-T therapies.

T cell engagers: new biotechs emerge

As clinical trials carry on, young startups like the U.S.-based Adaptin Bio, Clasp Therapeutics, and serial collaborator Candid Therapeutics, were launched in the past year to solely specialize in the T cell engager sector. With this class of drugs being assessed to address not only a range of cancers but also autoimmune conditions, its versatility in the therapeutic space could potentially be game-changing.

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