The emergence of the bispecific antibody (bsAb) offers an opportunity to combat resistance that arises following treatment of lung cancer with immunotherapy or targeted therapies.
By simultaneously binding two targets, these engineered antibodies have the potential to outmanoeuvre tumour escape pathways and fine-tune immune activation — moving us closer to more durable, personalised treatments.
What Is a Bispecific Antibody?
Standard antibodies use two arms to bind the same target, whereas bispecific antibodies have been engineered so each arm binds a different target simultaneously. The binding targets can be antigens, epitopes, or even cell surface markers such as specific membrane-bound proteins. This dual binding can achieve effects that traditional monoclonal antibodies cannot — such as blocking parallel signalling pathways, recruiting immune effector cells directly to tumours (see above), or bridging tumour and immune targets to overcome resistance. These bispecific antibodies bind to receptors that remain on the cell surface, but binding modulates downstream cell signalling pathways.
Bispecific antibodies come in several structural formats, with each structure designed to achieve a specific therapeutic goal. Compact formats such as BiTEs (bispecific T-cell engagers) create very strong T-cell activation but have a comparatively shorter half life. Bispecific antibodies that retain the full IgG structure — including the Fc region — have a long half-life, stable pharmacokinetics, and antibody-like behaviour with the added ability to bind two targets. Across these formats, the underlying engineering is tailored to match the intended mechanism — whether that is potent immune cell redirection, dual-pathway blockade, or enhanced tumour selectivity.
More than 180 bispecific antibodies are currently in development for cancer, and over 110 are in clinical trials. In lung cancer, three have already reached the clinic — including amivantamab, ivonescimab, and tarlatamab — marking a major inflection point in therapeutic innovation.
Functional Classes of Bispecific Antibodies in Lung Cancer
In lung cancer, two broad categories of bispecific antibodies have emerged:
Immune-targeting bispecifics, which modulate the immune system to restore anti-tumour responses.
Targeted-therapy bispecifics, which directly inhibit oncogenic signalling pathways.
1. Immune-Targeting Bispecific Antibodies
Immunotherapy has revolutionised NSCLC care, but resistance is common. Tumours can suppress T-cell activity through multiple immune checkpoints or evolve to exclude immune infiltration altogether. Bispecific antibodies are being developed to tackle this problem in two key ways.
a) Dual Checkpoint Inhibitors
These bispecific antibodies block two immune checkpoints simultaneously — for example, PD-L1 with CTLA-4 or PD-1 with TIGIT. By lifting multiple inhibitory “brakes” at once, they may achieve deeper immune activation than sequential or combined monotherapies, with potentially lower toxicity due to localised action in the tumour microenvironment.
PD-L1 × VEGF: Ivonescimab (AK112) is in Phase II–III HARMONi trials for NSCLC, combining anti-angiogenic effects with PD1-PDLI blockade
PD-1 × CTLA-4: Looking at dual checkpoint blockade, KN046 and AK104 are being clinically evaluated in NSCLC, including checkpoint-resistant settings.
PD-1 × TIGIT: Several agents are in Phase II trials, exploring reactivation of cytotoxic T cells in NSCLC where PD-1 therapy alone has failed. This bispecific antibody is also being explored in early phase mesothelioma trials.
These dual checkpoint bispecific antibodies may simplify combination immunotherapy, providing efficacy similar to ipilimumab–nivolumab while reducing overlapping toxicity.
b) Immune Cell-Engaging Bispecifics
Some bispecific antibodies bridge tumour cells and immune effector cells to trigger targeted killing. This is typically achieved by binding a tumour antigen on one arm and an activating receptor such as CD3 (on T cells) or CD16 (on NK cells) on the other.
In NSCLC, this approach is still emerging, but in small-cell lung cancer (SCLC) these agents have reached the clinic.
Tarlatamab, a DLL3 × CD3 bispecific T-cell engager, has demonstrated meaningful clinical activity in relapsed SCLC, and continues to be examined in clinical trials for earlier lines of SCLC treatment. You can hear more about tarlatamb in SCLC in our podcast on New Treatments and Emerging Standards in ES-SCLC.
Other constructs under development target EpCAM × CD3 and NK-cell engaging designs. As these evolve, immune cell engagers may complement checkpoint blockade in tumours that remain “cold” to immunotherapy.
2. Targeted-Therapy Bispecific Antibodies
Oncogene-driven NSCLC often develops resistance to tyrosine kinase inhibitors (TKIs) through activation of alternative growth pathways. Bispecific antibodies that target multiple receptor tyrosine kinases can disrupt these escape routes.
EGFR × MET: Amivantamab is the first bispecific antibody approved for NSCLC, indicated for EGFR exon 20 insertion mutations. It blocks ligand binding, promotes receptor internalisation and degradation, and induces macrophage- and NK-mediated cytotoxicity. By simultaneously targeting EGFR and MET, it helps overcome primary and secondary resistance mechanisms. Beyond Exon20 insertions, amivantamab is being explored in first-line combinations (e.g., MARIPOSA trials) and in EGFR-mutant resistance settings where MET pathway activation is a key escape mechanism.
EGFR × HER3 and VEGF × HER2: Emerging constructs under clinical evaluation aim to inhibit proliferative and angiogenic signalling simultaneously. These are not yet widely available in NSCLC but exemplify the expanding scope of targeted bispecific therapy.
Bispecific targeted antibodies may delay resistance, provide broader coverage than single-agent TKIs, and potentially improve durability of response.
Clinically Relevant Bispecific Antibodies
Bispecific antibody | Targets | Mechanism/Function | Clinical status |
|---|---|---|---|
Amivantamab | EGFR × MET | Blocks EGFR & MET signalling, promotes receptor internalisation/degradation, induces ADCC/trogocytosis | PBS-reimbursed for NSCLC harbouring EGFR Exon20 ins |
Ivonescimab (AK112) | PD-L1 × VEGF | Inhibits angiogenesis and blocks a checkpoint cascade | Phase II–III |
KN046 | PD-1 × CTLA-4 | Dual checkpoint blockade | Phase II–III |
AK104 | PD-1 × CTLA-4 | Dual checkpoint blockade | Phase II–III |
PD-1 × TIGIT bsAbs | PD-1 × TIGIT | Dual checkpoint blockade; restores T-cell cytotoxicity | Phase II |
Tarlatamab | DLL3 × CD3 | T-cell engager; directs cytotoxic T cells to DLL3-expressing tumour cells. | FDA-approved; clinical trials in Australia |
VEGF × HER2 bispecifics | VEGF × HER2 | Inhibits angiogenesis + HER2 growth signalling | Emerging / clinical development |
Bispecific Antibodies in Lung Cancer Clinical Practice
For clinicians, the significance of bispecific antibodies lies in how they translate biological precision into practical benefit. They offer:
More potent responses by removing two immune brakes or blocking parallel signalling pathways.
Potentially fewer overlapping toxicities than dual-drug combinations.
Simplified treatment delivery with two mechanisms embedded in a single molecule.
A strategy for overcoming resistance, particularly after PD-1 inhibitors or EGFR-TKIs.
In practice, bsAbs may be particularly relevant in patients with:
- disease progression after PD-1 therapy where T-cell exhaustion drives resistance (e.g. PD-1 × TIGIT),
- oncogene-driven NSCLC with MET-dependent bypass pathways (EGFR × MET), or
- SCLC with DLL3 expression where few effective options exist.
Early experience suggests that bispecific antibodies may reduce overlapping toxicities compared with two-drug combinations. However, target-specific effects remain relevant — for example, VEGF-related hypertension/proteinuria with ivonescimab, and cytokine-release syndrome with T-cell engagers like tarlatamab. Ongoing trials will determine whether dual-checkpoint bispecifics indeed offer a more favourable toxicity profile than ipilimumab–nivolumab-type combinations.
Looking Ahead
The bispecific antibody represents a natural next step in lung cancer therapeutics — a fusion of the immunotherapy and targeted therapy eras. With several agents already reaching Phase II–III in NSCLC, momentum is building fast.
Clinicians can expect these agents to be integrated into treatment algorithms, particularly for checkpoint-resistant and oncogene-driven disease. Continued clinical investigation will define their role in combination strategies, biomarker-guided selection, and overcoming therapeutic resistance.
In short, the bispecific antibody is more than just a new drug class — it’s a new design philosophy. By combining two mechanisms of action in one molecule, these therapies embody the principle of smart combination, simplified delivery, and hold genuine promise to reshape lung cancer care in the near future.
Bispecific Antibody Targets: A Quick Reference
Target | Type/category | Function / Relevance in NSCLC |
|---|---|---|
PD-1 | Immune checkpoint | Inhibitory receptor on T cells; binding PD-L1/PD-L2 suppresses T-cell activity. Blockade reactivates cytotoxic T cells. |
PD-L1 | Immune checkpoint ligand | Expressed on tumour and immune cells; engages PD-1 to suppress T-cell responses. Targeting restores anti-tumour immunity. |
CTL-A4 | Immune checkpoint | Inhibitory receptor on T cells; primarily regulates early T-cell activation via APC interaction. Blockade enhances T-cell priming. |
TIGIT | Immune checkpoint | Inhibitory receptor on T and NK cells; suppresses immune activation. Dual blockade with PD-1 can improve anti-tumour response. |
EGFR | Oncogenic receptor tyrosine kinase | Drives proliferation in EGFR-mutant NSCLC. Targeted by TKIs and bispecifics (e.g., EGFR × MET). |
MET | Oncogenic receptor tyrosine kinase | Activates bypass signalling leading to TKI resistance; targeted in EGFR × MET bispecifics. |
HER2 | Receptor tyrosine kinase | Drives growth signalling in HER2-amplified tumours; bispecifics with VEGF or HER3 under development. |
HER3 | Receptor tyrosine kinase | Often compensatory pathway in EGFR or MET resistance; targeted in EGFR × HER3 bispecifics. |
VEGF | Angiogenic factor | Stimulates tumour blood vessel growth; bispecifics combining VEGF with immune or HER2 blockade inhibit angiogenesis. |
DLL3 | Tumour antigen | Expressed on SCLC and some NSCLC cells; targeted by T-cell engagers (DLL3 × CD3). |
CD3 | T-cell co-receptor | Engages T cells; used in T-cell–redirecting bispecifics to mediate tumour cell killing. |
Listen to New and Emerging Practice Standards in ES-SCLC
Hear Dr Rebecca Tay, A/Prof Surein Arulananda and Dr Dasantha Jayamanne cover tarlatamab, a DLL3 xCD3 T cell engager showing substantial benefit in ES-SCLC.
Additional resources
Khosla, A. A., Jatwani, K., Singh, R., Reddy, A., Jaiyesimi, I., & Desai, A. (2023). Bispecific Antibodies in Lung Cancer: A State-of-the-Art Review. Pharmaceuticals, 16: 1461. https://doi.org/10.3390/ph16101461
