What are BiTEs, and Why Now?
Bispecific T-cell engagers (BiTEs) are a class of anti-cancer immunotherapeutics that redirect T cells to target cancer cells. BiTEs consist of the single-chain variable fragment (scFv) regions of two different monoclonal antibodies (mAbs) that are typically connected by a peptide linker. While one scFv binds to a tumour-associated antigen (TAA) on cancer cells and the other targets T cells (usually via CD3), this dual specificity promotes an immunological synapse, which leads to T cell activation, cytokine release, and targeted tumour cell lysis.
Despite the similar timing of initial approval of BiTEs and checkpoint inhibitors, BiTE uptake lagged behind that of checkpoint inhibitors due to the termination of several BiTE programs and the initial failure of BiTEs in targeting solid tumours. Though checkpoint inhibitors have shown success in targeting ‘hot’ tumours, their efficacy in targeting haematological malignancies and certain solid tumours remains constrained. BiTEs are emerging as a promising alternative to chemotherapy and checkpoint inhibitors, particularly in malignancies where immune evasion and T-cell exhaustion limit checkpoint inhibitor efficacy. While BiTEs have demonstrated clinical success in haematological cancers, their potential to target solid tumours is being actively pursued in a TAA-dependent manner, particularly following the accelerated approval of Amgen’s IMDELLTRA (targets DLL3) for extensive-stage small cell lung cancer (ES-SCLC).
Advantages and Challenges of BiTEs
BiTEs facilitate targeted killing of cancer cells with high specificity without requiring autologous patient-specific T cell engineering, thus enabling off-the-shelf availability (unlike CAR-T cell therapy). This facilitates more streamlined supply chain logistics for manufacturers, hence allowing patients to access treatment faster. The potential of BiTEs to be used in combination with other currently approved therapies, such as checkpoint inhibitors and chemotherapy, provides a crucial advantage by improving the precision of tumour targeting and overcoming T cell exhaustion, particularly when treating difficult-to-treat cancers.
Despite their success in haematological malignancies, several challenges limit the broader application of BiTEs, especially in solid tumours. These include continuous infusion (over several hours due to its short half-life), dose-limiting toxicities (DLTs), immune effector cell-associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), and the limited penetration of the immunosuppressive tumour microenvironment (TME). Setbacks in clinical development, such as the discontinuation of solitomab (solid tumours) and AMG 211 (advanced gastrointestinal cancers) due to toxicity and immunogenicity concerns, underscore the need for further optimisation in BiTEs.
What does the BiTE market look like?
BiTE’s, which are forecasted to generate ~$20.6 BN by 2030, are fast becoming a cornerstone of immunotherapy portfolios. BiTEs are transforming cancer care by improving the precision and efficacy of immunotherapy, particularly in haematological malignancies (e.g., multiple myeloma, follicular lymphoma) and some solid tumours (e.g., ES-SCLC, uveal melanoma).
Amgen, J&J, Regeneron, Roche and AbbVie are some key companies with approved BiTE assets. While most currently approved BiTEs are indicated for haematological malignancies, BiTEs indicated for non-haematological cancers are currently limited to IMDELLTRA and KIMMTRAK (Table 1).
Just as the success of BLINCYTO spurred the development of next-generation BiTEs that targeted a wide range of haematological malignancies, IMDELLTRA’s approval for ES-SCLC could revitalise interest and incentivise companies to continue pursuing BiTE development for solid tumours, which is an active area of research. In addition to some of the companies above (such as Amgen and Immunocore), other companies, such as Boehringer Ingelheim, are also exploring BiTEs in solid tumours, with Boehringer Ingelheim developing obrixtamig (BI 764532) for the treatment of small cell lung cancer (SCLC) and neuroendocrine carcinomas (NECs).
The Race to the Top of “BiTE Mountain”; Amgen vs J&J
While pharma companies pursue BiTEs, Amgen and J&J are key players in the BiTE space that continue to invest to optimise next-generation BiTE constructs, albeit adopting slightly different approaches. By 2030, BLINCYTO and IMDELLTRA are forecasted to generate $1.7 BN and $1.4 BN in sales, respectively (Source: GlobalData). However, J&J is predicted to be a leading force in the BiTE market and have the top-selling BiTEs by 2030, with TECVAYLI and TALVEY forecasted to generate global sales of $4.1 BN and $1.7 BN, respectively (Source: GlobalData).
Amgen is Pioneering BiTE Development
Amgen, which owns the BiTE platform, stands out as a pioneer in the BiTE landscape, evidenced by the clinical success and approval of BLINCYTO for treating B-ALL, as well as the accelerated approval of IMDELLTRA for ES-SCLC. This is further exemplified by its strong BiTE pipeline, which includes assets such as AMG 305 (CRC), AMG 330 (r/r AML), AMG 651 (solid tumours), and xaluritamig (prostate cancer), which targets both haematological malignancies and solid tumours.
Amgen’s journey with BiTEs reflects its strategic vision, which is driven by continuous innovation, key partnerships (e.g., Xencor), and deep internal expertise gathered by improving its BiTE platform that has supported the development of multiple oncology drug candidates. Amgen leverages peptide linker-connected scFv-based constructs in its BiTEs (e.g., BLINCYTO) and includes the Fc-region in more recent half-life extended (HLE) BiTEs (e.g., IMDELLTRA) to overcome challenges associated with the short half-life of initial BiTE designs.
Interestingly, Amgen terminated the pavurutamab program targeting multiple myeloma and is strategically not pursuing this indication using its BiTE platform. This decision was influenced by the highly competitive nature of the multiple myeloma market and Amgen’s focus on prioritising assets that have the potential to be “best-in-class or first-in-class”. The presence of other multiple myeloma assets, such as KYPROLIS and AMG-176, in Amgen’s portfolio further reinforces this strategic shift. While this strategy guides target and indication selection, an aggressive pursuit of first-to-target status could increase the risk of setbacks and asset discontinuation.
Despite setbacks from the termination of solid tumour programs such as AMG 211 and solitomab, the accelerated approval for ES-SCLC and the IMDELLTRA’s positive Ph3 DeLLphi-304 study readout in small cell lung cancer (SCLC) have helped to reignite interest for BiTEs in solid tumours and bolster Amgen’s position within the BiTE landscape. As Amgen invests in developing next-gen BiTEs, its extensive R&D and continuous communication through its website and corporate presentations showcase its commitment to advancing BiTE development. This solidifies its reputation and places it in a favourable position as a leading contender to set the benchmark in the BiTE landscape, particularly in solid tumours.
J&J is Banking on TECVAYLI and TALVEY
Unlike Amgen, which is optimising BiTE designs, J&J is utilising its vast resources, experience in antibody engineering, and partnerships (e.g. Genmab) to pave the way to the development of IgG-like BiTEs that include the Fc region by leveraging Genmab’s DuoBody platform. Though the Fc region inclusion offers superior stability due to its larger size and mitigates the rapid clearance rates typically seen in traditional BiTEs, its size makes it more challenging for the BiTEs to penetrate solid tumours. This is likely why J&J’s advanced BiTEs (i.e. TECVAYLI and TALVEY) have focused on targeting more lucrative chronic haematological malignancies (such as multiple myeloma) with a significant market opportunity.
J&J is also developing next-gen solid tumour-targeting BiTEs, such as JNJ-0387 (solid tumours), JNJ-2421 (solid tumours), JNJ-9401 (prostate cancer; in collaboration with Xencor), and JNJ-8343 (prostate cancer), which are potentially capable of penetrating solid tumours and exerting cytotoxicity. With readouts from J&J’s ongoing BiTE studies expected in 2026/2027, these results are poised to play a key role in influencing the prominence and strategic direction of J&J’s next-gen BiTEs in oncology.
The Final BiTE: Final Considerations and the Future of BiTEs
While BiTEs have been established as a treatment for haematological malignancies, their broader adoption in solid tumours remains to be seen. However, the IMDELLTRA approval and positive Ph3 DeLLphi-304 readout will likely trigger a paradigm shift and reignite optimism towards ongoing BiTE clinical studies across solid tumour types.
Given the allogenic ‘off-the-shelf’ potential and the relative ease of manufacturing BiTEs (vs CAR-T therapy), favourable readouts from ongoing studies are poised to position next-gen BiTEs as a key pillar of immuno-oncology treatment strategies, especially in haematological malignancies and solid tumours with limited treatment options.
What Should Companies Be Doing?
Pursuing precision oncology approaches by assessing biomarker expression using companion diagnostics
Aside from Immunocore’s KIMMTRAK, a biomarker-based precision medicine approach remains a white space. Companies should capitalise on this opportunity to integrate biomarker and companion diagnostic-driven precision medicine approaches in clinical trial designs for BiTEs. Doing so may enable the identification of patient subpopulations most likely to respond, thereby increasing the probability of clinical success while enhancing the return on R&D investments, particularly when targeting more challenging cancer types.
Targeting early lines of treatment, exploring combination therapy approaches, and developing indication sequencing roadmaps
Companies could explore opportunities to position BiTEs earlier in the treatment algorithm to avoid the risk of being displaced to later lines of therapy, as seen in multiple myeloma following CAR-T therapy entry. Additionally, exploring combination therapy approaches could enable companies to enhance value capture in cancer types requiring chronic treatment. While working closely with regulators, companies could consider well-characterised cancer types with validated targets as a launchpad for BiTEs before subsequently developing biomarker-based indication sequencing roadmaps to gradually position these BiTEs against more challenging tumours.
BiTEs are not just a scientific curiosity; they are fast becoming a competitive battleground. As the BiTE landscape evolves, particularly in solid tumours, companies should proactively stay abreast of the landscape to inform their strategy and identify white spaces to stay ahead of their competition. Companies that act now by embracing combination therapy strategies, prioritising regulatory agility, and investing in diagnostic integration will define the future of BiTEs in immuno-oncology.
Will the IMDELLTRA approval in ES-SCLC catalyse a paradigm shift that sets up BiTEs as a cornerstone in treating solid tumours? Will physicians and patients embrace BiTEs, and will insurers be willing to pay the price? We’d love to hear your thoughts.