Author: Suraj Kachgal
Associate Director, Business Development at Nona Biosciences
While antibody drug conjugates (ADCs) have been the darlings of biopharma for the past couple of years, dealmaking in the past month has shown renewed industry interest in T cell engagers (TCE). This diverse group generally consists of a multispecific, antibody-like molecule with at least one domain targeting a cell of interest (e.g. tumor cell, B cell) and another domain targeting T cells, typically via CD3 engagement. TCEs function to bring the two cell types in close proximity so as to induce T cell-mediated cytotoxicity of the cell of interest. The simplicity in manufacturing and administration, combined with their general tolerability, position TCEs as a leading therapeutic moiety in oncology and autoimmunity.
The Early Days of TCE and a Lull in the Action
The approval of ipilimumab in 2011 sparked a deluge of T cell-targeting immuno-oncology therapy development, which eventually led to another checkpoint inhibitor, Keytruda (pembrolizumab), becoming the best-selling cancer drug in 2023 with $25 billion worldwide. Three months after the first FDA approval of pembrolizumab in 2014, another T cell-targeting therapy with a different mechanism of action became the first approved TCE when Blincyto (blinatumomab) was cleared for the treatment of B cell precursor acute lymphoblastic leukemia (ALL). However, it would be over seven years before the FDA would issue the second TCE approval (tebentafusp for uveal melanoma, 2022). Within that time, the industry would see the emergence of chimeric antigen receptor (CAR)-T cell therapies, which represent a direct competitor to TCEs.
Between 2017-2018, Novartis and Kite received the first approvals for their CD19-directed CAR-T therapies for the treatment of certain types of non-Hodgkin lymphomas, and the subsequent years saw the approval of two BCMA-directed CAR-T products for the treatment of multiple myeloma. Novartis’ CAR-T product, Kymriah (tisagenlecleucel), received its first approval in B-cell ALL, similar to the TCE Blincyto, with the CAR-T delivering a 63% complete response rate (CRR) and >7.5 mos. median duration of response (mDOR) versus 34% and 6.7 mos. for the TCE, respectively; however, it should be noted that the Kymriah trial had significantly younger patients (median age: 12) compared to the Blincyto trial (median age: 37). Nevertheless, these early efficacy data likely led to a heightened focus on CAR-T development, and subsequent trials in other hematological cancers replicated the efficacy advantage of CAR-T. In the treatment of large B cell lymphoma, Kite’s CAR-T product, Yescarta (axicabtagene ciloleucel), produced a 65% CRR and 26.9 mos. mDOR, besting the results of the two TCEs, Columvi (glofitamab-gxbm) and Epkinly (epcoritamab-bysp), and in the most direct comparison of the two modalities, a pair of Johnson & Johnson, BCMA-directed, multiple myeloma therapies showed that their CAR-T, Carvykti (ciltacabtagene autolecel), produced a 74% CRR, better than the 28% of their TCE, Tecvayli (teclistamab). Notably, Carvykti is the first marketed CAR-T therapy that utilizes single domain antigen binders, specifically using two biparatopic VHHs joined by a linker.
TCEs Regaining Their Shine as CAR-T Loses its Luster
While the first slate of approved CAR-T represented a breakthrough for late-stage cancer patients, the practical challenges of CAR-T therapy became readily apparent. Whereas CAR-T trumps TCEs in efficacy, it severely lacks in safety. Nearly universally, TCEs have lower incidences of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) than their CAR-T counterparts, both overall and high-grade. Additionally, the preparatory lymphodepletion required for CAR-T therapy necessitates extended hospitalization due not only to CRS and ICANS, but also an increased risk of infection due to cytopenia. Consequently, a recent IQVIA survey of community oncologists listed patient frailty as a leading reason as to why they do not refer their patients for CAR-T treatment. Moreover, the complicated logistics of CAR-T administration limits it to a small number of tertiary care facilities that may necessitate significant patient travel. Adding in the hospital stays, preconditioning, and travel costs, the overall cost to the patient far exceeds the already-large sticker price of the CAR-T product, eliciting another toxicity—financial toxicity. When these toxicities are considered along with the fact that there is a significant rate of relapse following CAR-T therapy (30-60% for CD19-directed therapies), re-dosing becomes less palatable and the case for TCEs becomes stronger.
The ex vivo manufacturing process of current CAR-T products also presents several issues that limit further adoption. The complicated, multi-step process creates a long vein-to-vein time (>20 days) and increases the cost of goods far beyond antibody biologics. A recent Leerink Partners report stated that Gilead (which acquired Kite in 2017) is aiming to reduce manufacturing costs of its CAR-T products by 25% with a gross margin target of around 80% by 2030; this implies a current gross margin in the high 60 to low 70% range, far lower than that of bispecifics/TCEs, which can see greater than 80%. The ex vivo culture consequently reduces the stem-like character of the CAR-T cell product, thereby compromising efficacy and durability likely due to T cell exhaustion. This issue may be the primary reason why CAR-T efficacy in solid tumors has been severely lacking despite numerous clinical trials against a bevy of targets and why no CAR-T product for solid tumors has been approved to date.
Emerging TCE Approvals and Deals
The recent FDA approval of Amgen’s DLL3+CD3 TCE, Imdelltra (tarlatamab-dlle), for small cell lung cancer in May 2024, following the suspension of their parallel DLL3 CAR-T (AMG119) program in 2021, has sparked a wave of high-profile deals in the biopharma space over the past month. Daiichi Sankyo and Merck extended their existing ADC partnership to include Merck’s own DLL3 TCE candidate (MK6070) netting Merck $170 million upfront; MK6070 itself joined Merck’s pipeline, along with a host of other TCEs, through its $680 million Harpoon Therapeutics acquisition earlier this year. In quick succession, Merck also acquired the worldwide rights to a Phase II TCE targeting CD19+CD3 from the China-based Curon Biopharma for $700 million upfront and potentially $1.3 billion overall. In the same week, it was announced that Vir Biotech licensed worldwide commercial rights from Sanofi to three TCEs targeting HER2, PSMA, and EGFR for $100 million upfront in a deal potentially totaling $2 billion.
Autoimmunity: The Next Frontier
While much of the focus on CAR-T and TCEs has been in oncology, proof-of-concept research from Dr. Georg Schett’s lab demonstrating the efficacy of CD19-directed CAR-T therapy in a small number of autoimmune patients has created a stampede of companies expanding their CAR-T and TCE candidates into numerous immunology clinical trials. Of critical note, Schett’s work demonstrated that a one-time CAR-T administration provided for the resolution of symptoms beyond two years and the discontinuation of immunosuppressive therapy even after the re-emergence of B cells; this implies that a B cell reset can provide a meaningful and lasting clinical improvement. As such, this shifts the risk-benefit equation in favor of TCEs as the risks of CRS, ICANS, and lymphodepletion with CAR-T become amplified in autoimmunity where prognoses are generally more favorable than in oncology. Indeed, these risks are being realized in the current CAR-T autoimmune trials as earlier this month, Cabaletta Bio reported a Grade 4 ICANS event in their CAR-T trial for lupus, while earlier this year Kyverna reported that from their compiled trials across multiple autoimmune indications, 10% (3/30) of treated patients experienced low-grade ICANS and 83% (25/30) experienced low-grade CRS.
In the press release announcing the Curon asset acquisition, Merck explicitly stated their plans to test their new CD19 TCE in autoimmune diseases, and the large upfront payment highlights the safety benefit that TCEs provide. The deal comes in the wake of Curon’s American Society of Clinical Oncology presentation of their Phase I data in which they announced that out of 58 non-Hodgkin lymphoma patients, only 4 (7%) showed low-grade CRS and none showed ICANS; this is superior to the clinically-approved Blincyto: 17% CRS (3% high-grade) and 8% ICANS. The compelling safety data are no coincidence as Curon specifically engineered a CD3 engager with low affinity to moderate T cell activation and prevent overstimulation and a cytokine storm.
Innovation and Development
With TCEs in the spotlight, Nona Biosciences can enable and empower the efficient development of the next-generation TCEs. Nona possesses a vast library of natural killer and T cell engagers, including CD3 binders with optimized CD3 binding affinity to reduce the potential for CRS and ICNAS like Curon’s CD3 binder; our lead CD3 clone (which is available for licensing) forms the T cell engaging arm of two clinical candidates, including AstraZeneca’s AZD5863 (CLDN18.2+CD3). Furthermore, we have multiple CD3 binders that have cynomolgus cross-reactivity, thereby enabling our partners to conduct non-human primate toxicology/efficacy studies without having to alter their drug product. We also have single domain CD3 binders in which the lack of a light chain allows for more flexible multispecific antibody geometries to allow for improved crosslinking, clustering, and immune synapse distancing. Single domain antibodies have the added benefit of not being subject to light chain mispairing, thereby allowing for efficient multispecific antibody engineering. Of note, Nona possesses the only available single domain CD3 antibody that is cynomolgus cross-reactive. These single domain binders form the basis of Nona’s HBICE® platform. Nona also offers a unique library of TCE assets and expertise in antibody engineering, making it a valuable partner in the development of cutting-edge therapeutic antibodies.
