Introduction
The therapeutic landscape of oncology has been fundamentally reshaped by sophisticated antibody-based platforms, moving beyond simple blockade of cell-surface receptors to precise delivery of cytotoxic payloads and redirection of immune effector cells. This evolution is epitomized by the clinical maturation of two distinct yet complementary modalities: antibody–drug conjugates (ADCs) and bispecific antibodies (bsAbs). ADCs, often described as “biological missiles,” exploit the specificity of monoclonal antibodies to deliver highly potent cytotoxic agents directly to tumor cells, aiming to widen the therapeutic index of traditional chemotherapy [ 1 ]. The conceptual and technical progress in this field, spanning over four decades, has yielded transformative clinical successes, yet it has also exposed persistent challenges related to target selection, payload diversification, and management of unique toxicity profiles [ 2 , 3 ]. Concurrently, bispecific antibodies have emerged as a mechanistically distinct class capable of engaging two different antigens or epitopes simultaneously, enabling novel functions such as retargeting of T cells to cancer cells, dual checkpoint blockade, or co-targeting of tumor antigens and co-stimulatory receptors [ 4 – 6 ].
The clinical impact of these agents is most vividly illustrated in hematological malignancies. In multiple myeloma (MM), identification of B-cell maturation antigen (BCMA) as a near-universal target on malignant plasma cells has catalyzed a new therapeutic arsenal. The BCMA-targeting ADC belantamab mafodotin demonstrated feasibility, achieving meaningful responses in heavily pretreated patients, though with notable keratopathy, an off-target toxicity attributed to MMAF-related effects on corneal epithelium rather than on-target BCMA engagement [ 7 , 8 ]. This proof-of-concept has been rapidly succeeded by T-cell redirecting bsAbs such as teclistamab and elranatamab, which have shown remarkable efficacy in triple-class refractory disease, with overall response rates exceeding 60% and durable remissions, albeit with class-specific challenges of cytokine release syndrome (CRS) and infections [ 9 , 10 ]. The field is advancing beyond BCMA, with G protein-coupled receptor class C group 5 member D (GPRC5D) and Fc receptor-homolog 5 (FcRH5) emerging as validated targets for bsAbs like talquetamab and cevostamab, providing critical salvage options and highlighting the potential of antigen-agnostic T-cell engagement [ 11 – 13 ]. A meta-analysis comparing these T-cell redirecting platforms suggests that while chimeric antigen receptor (CAR) T-cell therapy may offer higher complete response rates, bsAbs provide an off-the-shelf, readily available alternative with a distinct safety profile, underscoring the need for nuanced patient selection [ 14 ].
A parallel revolution is unfolding in B-cell non-Hodgkin lymphomas (B-NHL). The CD19-directed ADC loncastuximab tesirine has provided a new option for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) [ 15 , 16 ], while integration of polatuzumab vedotin, a CD79b-targeting ADC, into frontline therapy (Pola-R-CHP) has become the first regimen in decades to improve progression-free survival over R-CHOP in DLBCL [ 17 , 18 ]. The CD20×CD3 bsAbs, including mosunetuzumab, epcoritamab, and glofitamab, have further expanded the armamentarium, demonstrating high complete response rates and durable remissions in relapsed/refractory follicular lymphoma and DLBCL, even in patients progressing after CAR T-cell therapy [ 19 – 22 ]. The combination of these modalities, such as mosunetuzumab with polatuzumab vedotin, is a burgeoning strategy aiming for synergistic antitumor activity by targeting both the malignant B cell and the immune microenvironment [ 23 ]. In Hodgkin lymphoma, the CD30-targeting ADC brentuximab vedotin (BV) has become a cornerstone, demonstrating significant benefits in frontline (ECHELON-1) and relapsed settings, and is now combined with immune checkpoint inhibitors like nivolumab to further improve outcomes [ 24 – 26 ].
The paradigm shift is equally profound in solid tumors, where ADCs have redefined targeted therapy. Trastuzumab deruxtecan (T-DXd), a HER2-targeting ADC with a topoisomerase I inhibitor payload and a cleavable linker enabling potent bystander killing, has been a trailblazer. Its clinical activity has shattered the traditional binary HER2 classification, demonstrating significant overall survival benefits in HER2-low metastatic breast cancer—a population previously ineligible for HER2-targeted therapies [ 27 , 28 ]. T-DXd has also shown remarkable intracranial activity in patients with HER2-positive breast cancer brain metastases, a site of high unmet need [ 29 , 30 ]. This success has spurred investigation across a pan-tumor landscape, including HER2-mutant non-small-cell lung cancer (NSCLC) and HER2-expressing colorectal and gastric cancers, establishing a new paradigm of biomarker-informed, histology-agnostic therapy [ 31 – 34 ]. The clinical progress of ADCs is further evidenced by approvals of agents targeting TROP-2 (sacituzumab govitecan), Nectin-4 (enfortumab vedotin), and tissue factor (tisotumab vedotin) in breast, urothelial, and cervical cancers, respectively, validating the broad applicability of this platform [ 35 – 37 ].
Bispecific antibodies are also making significant inroads in solid tumor oncology. The EGFR-MET bsAb amivantamab has demonstrated efficacy in overcoming resistance to third-generation EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC, a setting with no previously approved targeted therapies [ 38 ]. The PD-1/CTLA-4 bispecific antibody cadonilimab has shown promising activity and a manageable safety profile across multiple advanced solid tumors, leading to its approval in gastric cancer and highlighting the potential of dual checkpoint blockade within a single molecule [ 39 – 41 ]. Furthermore, the HER2-targeted bsAb zanidatamab has shown compelling activity in HER2-amplified biliary tract cancer, a rare tumor type with limited options, and is being explored in first-line gastro-esophageal adenocarcinoma [ 42 – 44 ]. The next frontier involves bispecific constructs engaging tumor-associated antigens on solid tumors with CD3 on T cells, such as the DLL3-targeting tarlatamab in small-cell lung cancer, which has shown durable responses and is being evaluated in the maintenance setting [ 45 , 46 ].
Despite these remarkable advances, the evolving paradigm is confronted by significant challenges. Management of unique and sometimes severe toxicities, including CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and off-target effects like interstitial lung disease with certain ADCs, requires standardized protocols and vigilant monitoring [ 47 – 49 ]. A critical and unresolved issue is resistance development, driven by mechanisms such as antigen loss or downregulation, payload efflux, and T-cell exhaustion, which ultimately limits response durability to both ADCs and bsAbs [ 50 – 52 ]. Identification of robust predictive biomarkers beyond target antigen expression remains an urgent priority, as evidenced by the variable correlation between TROP-2 expression and response to TROP-2 ADCs, and the emerging role of immune fitness in predicting outcomes with T-cell engagers [ 53 – 55 ]. Optimal sequencing of these powerful agents with each other and with cellular therapies like CAR T-cells is a complex, unanswered question that will define future treatment algorithms [ 56 , 57 ].
The body of evidence reviewed here underscores a fundamental transition in oncology from systemic, non-specific cytotoxic agents to a sophisticated armamentarium of immune-engaging and tumor-targeted biologics. The success of agents like T-DXd and T-cell redirecting bsAbs validates achieving a high therapeutic index through deep mechanistic understanding of tumor biology, yet a persistent uncertainty lies in the generalizability of this success from hematologic malignancies to solid tumors, where the immunosuppressive microenvironment, physical barriers to T-cell infiltration, and scarcity of truly tumor-specific surface antigens present formidable obstacles. Contradictory findings regarding the predictive value of target antigen expression for ADCs expose a major methodological weakness, while rapid emergence of antigen escape mutations reveals a fundamental vulnerability of single-antigen-directed immunotherapies. The proliferation of trials with non-contemporary control arms and selective enrollment further hinders clear assessment of the true added value of these novel agents, making cross-trial comparisons and clinical decision-making increasingly difficult.
Clinical development of HER2-directed ADCs in solid tumors
The clinical development of HER2-directed antibody-drug conjugates (ADCs) has fundamentally altered the treatment paradigm for HER2-altered solid tumors, expanding beyond traditional HER2-positive breast and gastric cancers to encompass HER2-low, HER2-mutant, and even HER2-non-expressing malignancies. Trastuzumab deruxtecan (T-DXd), a HER2-directed ADC with a topoisomerase I inhibitor payload and a cleavable linker, has demonstrated unprecedented efficacy across a spectrum of HER2 expression levels and tumor types. In the phase 2 DAISY trial, T-DXd achieved confirmed objective response rates (ORR) of 70.6% in HER2-overexpressing, 37.5% in HER2-low, and 29.7% in HER2-non-expressing metastatic breast cancer, challenging the conventional binary HER2 classification and highlighting the role of bystander killing and payload delivery even with minimal target expression [ 58 ]. The long-term survival analysis of DESTINY-Breast03 confirmed the superiority of T-DXd over trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer, with a median progression-free survival (PFS) of 29.0 months versus 7.2 months (hazard ratio 0.30) and a significant overall survival benefit [ 59 ]. In the HER2-low setting, DESTINY-Breast04 established T-DXd as a standard of care, demonstrating a median overall survival of 22.9 months versus 16.8 months with chemotherapy (hazard ratio 0.69) after extended follow-up [ 28 ] (Table 1 ).
The intracranial activity of T-DXd has been a particularly important advance. The phase 2 TUXEDO-1 trial reported an intracranial response rate of 73.3% in patients with HER2-positive breast cancer and active brain metastases, providing prospective evidence of central nervous system (CNS) penetration [ 29 ]. This was further supported by the phase 3b/4 DESTINY-Breast12 study, which confirmed intracranial activity in a larger cohort [ 30 ]. Critically, the DEBBRAH trial evaluated T-DXd in patients with HER2-positive and HER2-low breast cancer with leptomeningeal carcinomatosis, a devastating complication with extremely limited treatment options, and demonstrated clinically meaningful activity, with a median overall survival of 11.3 months in cohort 5 [ 60 ]. This represents a paradigm shift, as systemic therapies have historically shown minimal efficacy in leptomeningeal disease.
Beyond breast cancer, T-DXd has reshaped the treatment of HER2-positive gastric and gastroesophageal junction (G/GEJ) cancers. The phase 2 DESTINY-Gastric01 trial demonstrated a significant improvement in response and overall survival compared with chemotherapy in Asian patients, leading to initial approvals [ 61 ]. The DESTINY-Gastric02 trial confirmed these findings in Western populations, with an ORR of 38% and a median overall survival of 12.1 months in patients who had progressed on trastuzumab-containing regimens [ 62 ]. In colorectal cancer, the DESTINY-CRC01 trial showed promising activity in HER2-positive, RAS wild-type tumors, with an ORR of 45.3% in the 6.4 mg/kg cohort [ 32 ]. The subsequent DESTINY-CRC02 trial refined the dosing strategy, establishing 5.4 mg/kg as the recommended dose with an ORR of 37.8% and a median duration of response of 5.5 months, and importantly demonstrated activity in both RAS wild-type and mutant subgroups [ 34 ].
In non-small cell lung cancer (NSCLC), T-DXd has shown efficacy in both HER2-mutant and HER2-overexpressing cohorts. The DESTINY-Lung01 trial reported an ORR of 26.5% in HER2-overexpressing NSCLC with the 6.4 mg/kg dose, though with notable toxicity including interstitial lung disease (ILD) [ 63 ]. The DESTINY-PanTumor01 trial expanded the indication to HER2-mutant solid tumors beyond lung cancer, demonstrating an ORR of 29.4% across various tumor types, validating HER2 mutations as an actionable target for ADC therapy [ 33 ].
Next-generation HER2-directed ADCs are emerging with distinct design features. Trastuzumab rezetecan (SHR-A1811), a HER2-directed ADC with a topoisomerase I inhibitor payload, has shown promising activity in HER2-mutant NSCLC. The phase 2 HORIZON-Lung trial reported an ORR of 38.6% and a median PFS of 9.5 months in heavily pretreated patients, with a manageable safety profile [ 64 ]. The global phase 1 HORIZON-X trial further demonstrated the broad antitumor activity of SHR-A1811 across HER2-expressing or mutated advanced solid tumors, with durable responses observed in breast, gastric, lung, and colorectal cancers [ 65 ]. Notably, translational analyses from the neoadjuvant FASCINATE-N trial revealed that spatial determinants, such as immune cell infiltration in hormone receptor-negative tumors and HER2-positive tumor cell aggregation in hormone receptor-positive tumors, may predict response to SHR-A1811, underscoring the complexity of ADC biomarkers beyond simple HER2 expression [ 66 ].
ARX788, a site-specific, construct-homogeneous HER2-directed ADC with a microtubule inhibitor payload, has demonstrated efficacy in HER2-positive advanced breast cancer. The phase 3 ACE-Breast-02 trial compared ARX788 with lapatinib plus capecitabine in patients who had progressed on trastuzumab-based therapy, showing a significant improvement in PFS (hazard ratio 0.64) and a trend toward improved overall survival, with a distinct toxicity profile characterized by ocular and pulmonary events [ 67 ]. In HER2-positive advanced gastric cancer, a phase 1 dose-expansion study of ARX788 reported an ORR of 37.9% and a median PFS of 4.1 months in trastuzumab-refractory patients, indicating activity in this difficult-to-treat population [ 68 ].
The clinical development of these HER2-directed ADCs has been accompanied by a critical re-evaluation of HER2 testing paradigms. The advent of HER2-low as a clinically actionable category, driven by the efficacy of T-DXd, has necessitated more sensitive and quantitative immunohistochemistry assays to distinguish HER2-low from HER2-absent tumors, as the DAISY trial suggested that even HER2-non-expressing tumors may derive some benefit, albeit with lower response rates [ 58 , 69 ].
The body of evidence reviewed here establishes HER2-directed ADCs, particularly T-DXd, as one of the most transformative classes of anticancer agents in the past decade. The most promising finding is the consistent intracranial and leptomeningeal activity, which addresses a critical unmet need in patients with CNS involvement, a population historically excluded from or poorly served by systemic therapies. The demonstration that T-DXd can achieve meaningful responses in leptomeningeal disease, as shown in the DEBBRAH trial, is a genuine breakthrough. However, several uncertainties and methodological weaknesses temper these advances. First, the reliance on single-arm phase 2 trials for many indications, including intracranial activity and leptomeningeal disease, limits the strength of evidence; randomized comparisons against standard-of-care CNS-directed therapies are lacking. Second, the optimal sequencing of HER2-directed ADCs with other HER2-targeted agents, including tyrosine kinase inhibitors and bispecific antibodies, remains undefined, and the mechanisms of acquired resistance to these ADCs are poorly understood (see Safety, Resistance, and Sequencing section). Third, the toxicity profile of T-DXd, particularly ILD, remains a significant clinical challenge, and the risk-benefit ratio in HER2-low or HER2-non-expressing tumors requires careful consideration, as the absolute benefit in these populations is modest. Finally, the generalizability of data from Asian-predominant trials, such as DESTINY-Gastric01 and HORIZON-Lung, to global populations requires confirmation, as differences in pharmacokinetics, toxicity, and tumor biology may influence outcomes. The next generation of HER2-directed ADCs, including trastuzumab rezetecan and ARX788, offer distinct payload and linker chemistries that may overcome some resistance mechanisms and improve tolerability, but their comparative efficacy against T-DXd has not been established in head-to-head trials. The field urgently needs randomized phase 3 trials in CNS-predominant disease, biomarker-driven strategies to select patients most likely to benefit from specific ADCs, and rational combination regimens that leverage the immunomodulatory effects of ADC payloads.
Table 1 Key clinical trials of trastuzumab deruxtecan across HER2-altered solid tumors Tumor type HER2 status Trial name Key efficacy outcome Citation Metastatic breast cancer HER2-overexpressing DAISY ORR 70.6% [ 58 ] Metastatic breast cancer HER2-low DAISY ORR 37.5% [ 58 ] Metastatic breast cancer HER2-non-expressing DAISY ORR 29.7% [ 58 ] Metastatic breast cancer HER2-positive DESTINY-Breast03 Median PFS 29.0 vs. 7.2 months (HR 0.30) [ 59 ] Metastatic breast cancer HER2-low DESTINY-Breast04 Median OS 22.9 vs. 16.8 months (HR 0.69) [ 28 ] Breast cancer with brain metastases HER2-positive TUXEDO-1 Intracranial response rate 73.3% [ 29 ] Breast cancer with brain metastases HER2-positive DESTINY-Breast12 Confirmed intracranial activity [ 30 ] Breast cancer with leptomeningeal carcinomatosis HER2-positive/HER2-low DEBBRAH Median OS 11.3 months (cohort 5) [ 60 ] Gastric/GEJ cancer HER2-positive DESTINY-Gastric01 Improved response and OS vs. chemotherapy [ 61 ] Gastric/GEJ cancer HER2-positive DESTINY-Gastric02 ORR 38%, median OS 12.1 months [ 62 ] Colorectal cancer HER2-positive, RAS WT DESTINY-CRC01 ORR 45.3% (6.4 mg/kg) [ 32 ] Colorectal cancer HER2-positive DESTINY-CRC02 ORR 37.8% (5.4 mg/kg) [ 34 ] NSCLC HER2-overexpressing DESTINY-Lung01 ORR 26.5% (6.4 mg/kg) [ 63 ] Pan-tumor HER2-mutant DESTINY-PanTumor01 ORR 29.4% [ 33 ]
Table 1
Key clinical trials of trastuzumab deruxtecan across HER2-altered solid tumors
| Tumor type | HER2 status | Trial name | Key efficacy outcome | Citation |
| Metastatic breast cancer | HER2-overexpressing | DAISY | ORR 70.6% | [ 58 ] |
| Metastatic breast cancer | HER2-low | DAISY | ORR 37.5% | [ 58 ] |
| Metastatic breast cancer | HER2-non-expressing | DAISY | ORR 29.7% | [ 58 ] |
| Metastatic breast cancer | HER2-positive | DESTINY-Breast03 | Median PFS 29.0 vs. 7.2 months (HR 0.30) | [ 59 ] |
| Metastatic breast cancer | HER2-low | DESTINY-Breast04 | Median OS 22.9 vs. 16.8 months (HR 0.69) | [ 28 ] |
| Breast cancer with brain metastases | HER2-positive | TUXEDO-1 | Intracranial response rate 73.3% | [ 29 ] |
| Breast cancer with brain metastases | HER2-positive | DESTINY-Breast12 | Confirmed intracranial activity | [ 30 ] |
| Breast cancer with leptomeningeal carcinomatosis | HER2-positive/HER2-low | DEBBRAH | Median OS 11.3 months (cohort 5) | [ 60 ] |
| Gastric/GEJ cancer | HER2-positive | DESTINY-Gastric01 | Improved response and OS vs. chemotherapy | [ 61 ] |
| Gastric/GEJ cancer | HER2-positive | DESTINY-Gastric02 | ORR 38%, median OS 12.1 months | [ 62 ] |
| Colorectal cancer | HER2-positive, RAS WT | DESTINY-CRC01 | ORR 45.3% (6.4 mg/kg) | [ 32 ] |
| Colorectal cancer | HER2-positive | DESTINY-CRC02 | ORR 37.8% (5.4 mg/kg) | [ 34 ] |
| NSCLC | HER2-overexpressing | DESTINY-Lung01 | ORR 26.5% (6.4 mg/kg) | [ 63 ] |
| Pan-tumor | HER2-mutant | DESTINY-PanTumor01 | ORR 29.4% | [ 33 ] |
Expanding the ADC landscape: novel payloads and antigen targets
The clinical success of antibody-drug conjugates (ADCs) targeting established antigens such as HER2 has catalyzed the development of agents directed against a broader array of tumor-associated targets, including TROP2, CLDN18.2, B7-H3, HER3, and CEACAM5, across a spectrum of solid tumors. These novel ADCs are not only expanding the treatable patient population but are also pioneering the use of next-generation payloads and bispecific constructs to overcome therapeutic resistance and tumor heterogeneity. (Table 2 )
TROP2-targeted ADCs in non-small cell lung and breast cancers
Trophoblast cell-surface antigen 2 (TROP2) has emerged as a compelling target in multiple epithelial cancers. Sacituzumab tirumotecan (sac-TMT), a novel TROP2-directed ADC with a belotecan-derived topoisomerase I inhibitor payload, has demonstrated significant activity. In a phase 3 trial for previously treated metastatic triple-negative breast cancer (TNBC), sac-TMT significantly improved progression-free survival (PFS) compared to chemotherapy (median PFS 6.7 vs. 2.5 months; HR 0.32) [ 70 ]. In advanced non-small-cell lung cancer (NSCLC), sac-TMT showed a confirmed objective response rate (ORR) of 40%, with particularly encouraging activity in the EGFR-mutant subset (ORR 55%, median PFS 11.1 months) [ 71 ]. The combination of sac-TMT with the anti-PD-L1 antibody tagitanlimab as first-line therapy in advanced NSCLC is also being explored, with initial phase 2 data showing promising antitumor activity [ 72 ]. Another TROP2-directed ADC, datopotamab deruxtecan (Dato-DXd), is being evaluated in early-stage breast cancer within the I-SPY2.2 platform trial, both as monotherapy and in combination with durvalumab, where it has shown the ability to achieve high rates of pathologic complete response (pCR) in selected high-risk subtypes [ 73 , 74 ]. However, the phase 2 ICARUS-LUNG01 study in pretreated advanced NSCLC reported a more modest ORR of 26.0% for Dato-DXd, with a median PFS of 3.6 months, and suggested that a lack of TROP2 cytoplasmic staining and early activation of DNA repair pathways may be associated with resistance [ 75 ]. This highlights the critical need for predictive biomarkers to guide TROP2-ADC therapy.
CLDN18.2 as a therapeutic target in gastric and gastroesophageal cancers
Claudin 18.2 (CLDN18.2) is a tight junction protein exposed on the surface of gastric cancer cells, making it an attractive target. The phase 1 trial of the CLDN18.2-targeting ADC IBI343, which delivers a topoisomerase I inhibitor exatecan payload, enrolled 127 patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma and demonstrated a manageable safety profile with dose-limiting toxicities observed at the highest dose level [ 76 ]. Similarly, SHR-A1904, another CLDN18.2-targeting ADC with a topoisomerase I inhibitor payload, showed promising antitumor activity in a phase 1 study of 95 previously treated patients with CLDN18.2-positive advanced G/GEJ cancer [ 77 ]. The ADC CMG901, which uses a microtubule-disrupting monomethyl auristatin E (MMAE) payload, also demonstrated encouraging efficacy and a tolerable safety profile in a phase 1 trial that included patients with advanced G/GEJ cancer [ 78 ]. These data collectively validate CLDN18.2 as a viable ADC target, with the choice of payload potentially influencing both the efficacy and toxicity profile in this disease.
Targeting B7-H3, HER3, and CEACAM5 in solid tumors
B7-H3 (CD276) is a pan-tumor antigen being actively pursued with multiple ADCs. The phase 1/1b trial of YL201, a B7-H3-targeting ADC with a novel topoisomerase I inhibitor, enrolled 312 patients across various solid tumors and established a maximum tolerated dose, with early signs of efficacy observed in extensive-stage small cell lung cancer (ES-SCLC) and nasopharyngeal carcinoma [ 79 ]. Ifinatamab deruxtecan, another B7-H3-directed ADC using the deruxtecan platform, showed a manageable safety profile in a phase 1/2 dose-escalation trial [ 80 ]. In lung cancer, the B7-H3-targeted ADC HS-20,093 demonstrated a confirmed ORR of 52.3% in ES-SCLC and 22.4% in NSCLC, though treatment-related interstitial lung disease was a notable safety concern [ 81 ].
HER3 (ERBB3) has been successfully targeted by patritumab deruxtecan (HER3-DXd). The TUXEDO-3 trial demonstrated the intracranial activity of HER3-DXd in patients with active brain metastases from breast cancer and NSCLC, meeting its primary endpoint in both cohorts and validating the ability of this ADC to penetrate the central nervous system [ 82 , 83 ]. Furthermore, HER3-DXd showed efficacy in patients with leptomeningeal metastatic disease from solid tumors [ 84 ]. The ICARUS-BREAST01 phase 2 study in HR+ breast cancer explored biomarkers of response and resistance to HER3-DXd, underscoring the ongoing effort to refine patient selection for this agent [ 85 ].
CEACAM5 is another emerging target, particularly in colorectal cancer (CRC). Precemtabart tocentecan, an anti-CEACAM5 ADC with an exatecan payload, was evaluated in a phase 1 trial of heavily pretreated, irinotecan-refractory metastatic CRC patients, showing a tolerable safety profile and early signals of antitumor activity [ 86 ].
Bispecific ADC constructs and novel payload strategies
The development of bispecific ADCs represents a frontier in overcoming tumor heterogeneity and resistance. BL-B01D1, a first-in-class bispecific ADC targeting both EGFR and HER3 with a topoisomerase I inhibitor payload, has shown promising results. In a phase 1b trial for metastatic esophageal squamous cell carcinoma (ESCC), BL-B01D1 demonstrated robust antitumor activity in a heavily pretreated population [ 87 ]. A broader first-in-human phase 1 study of BL-B01D1 across multiple solid tumor types confirmed its potential, establishing a recommended phase 2 dose and showing durable responses in several tumor cohorts [ 88 ]. This bispecific approach aims to enhance tumor selectivity and overcome the limitations of single-antigen targeting.
The diversification of ADC payloads beyond traditional microtubule inhibitors and DNA-damaging agents is also a key area of innovation. The field is moving towards payloads with distinct mechanisms, such as topoisomerase I inhibitors (e.g., exatecan and deruxtecan), which have been central to the success of agents like trastuzumab deruxtecan and are now being incorporated into many of the novel ADCs discussed. Other strategies include immune-stimulating ADCs and protein-degrader ADCs, which are in earlier stages of clinical development but hold the potential to engage the immune system or degrade target proteins directly [ 89 , 90 ].
The rapid expansion of the ADC landscape into new antigen targets and bispecific constructs is generating impressive clinical data, particularly for TROP2-ADCs in breast and lung cancers and CLDN18.2-ADCs in gastric cancer. The most promising approaches appear to be those that leverage potent, membrane-permeable payloads like topoisomerase I inhibitors, which enable a bystander killing effect to address antigen heterogeneity. However, the field faces significant uncertainties. The variable efficacy of TROP2-ADCs in NSCLC, where the ICARUS-LUNG01 biomarker analysis points to the need for functional biomarkers of payload sensitivity, underscores that patient selection based solely on antigen expression is insufficient. For bispecific constructs like BL-B01D1, the added complexity of targeting two antigens may improve efficacy but also raises questions about increased toxicity and the optimal setting for use. Methodologically, the lack of standardized, validated predictive biomarkers across all ADC programs remains a critical weakness, as most trials enroll patients based on antigen expression without a clear understanding of the downstream determinants of response, such as payload sensitivity, internalization rates, or tumor microenvironment factors. The true promise of these novel ADCs will only be realized when paired with robust companion diagnostics that can identify the patients most likely to benefit.
Table 2 Novel ADCs and their targets, payloads, and clinical findings in solid tumors ADC Name Target Antigen Payload Cancer Type Key Clinical Finding Citation Sacituzumab tirumotecan (sac-TMT) TROP2 Belotecan-derived topoisomerase I inhibitor Metastatic TNBC Improved PFS vs. chemotherapy (median 6.7 vs. 2.5 months; HR 0.32) [ 70 ] Sacituzumab tirumotecan (sac-TMT) TROP2 Belotecan-derived topoisomerase I inhibitor Advanced NSCLC Confirmed ORR 40%; EGFR-mutant subset ORR 55%, median PFS 11.1 months [ 71 ] Sacituzumab tirumotecan (sac-TMT) + tagitanlimab TROP2 Belotecan-derived topoisomerase I inhibitor Advanced NSCLC (1 L) Promising antitumor activity in phase 2 [ 72 ] Datopotamab deruxtecan (Dato-DXd) TROP2 DXd topoisomerase I inhibitor Early-stage breast cancer High pCR rates in high-risk subtypes (I-SPY2.2) [ 73 , 74 ] Datopotamab deruxtecan (Dato-DXd) TROP2 DXd topoisomerase I inhibitor Pretreated advanced NSCLC ORR 26.0%, median PFS 3.6 months; resistance linked to low TROP2 staining and DNA repair activation [ 75 ] IBI343 CLDN18.2 Exatecan topoisomerase I inhibitor Advanced G/GEJ adenocarcinoma Manageable safety; DLTs at highest dose level [ 76 ] SHR-A1904 CLDN18.2 Topoisomerase I inhibitor CLDN18.2 + advanced G/GEJ cancer Promising antitumor activity in phase 1 [ 77 ] CMG901 CLDN18.2 MMAE (microtubule inhibitor) Advanced G/GEJ cancer Encouraging efficacy and tolerable safety [ 78 ] YL201 B7-H3 Novel topoisomerase I inhibitor Various solid tumors (ES-SCLC, NPC) MTD established; early efficacy in ES-SCLC and NPC [ 79 ]
Table 2
Novel ADCs and their targets, payloads, and clinical findings in solid tumors
| ADC Name | Target Antigen | Payload | Cancer Type | Key Clinical Finding | Citation |
| Sacituzumab tirumotecan (sac-TMT) | TROP2 | Belotecan-derived topoisomerase I inhibitor | Metastatic TNBC | Improved PFS vs. chemotherapy (median 6.7 vs. 2.5 months; HR 0.32) | [ 70 ] |
| Sacituzumab tirumotecan (sac-TMT) | TROP2 | Belotecan-derived topoisomerase I inhibitor | Advanced NSCLC | Confirmed ORR 40%; EGFR-mutant subset ORR 55%, median PFS 11.1 months | [ 71 ] |
| Sacituzumab tirumotecan (sac-TMT) + tagitanlimab | TROP2 | Belotecan-derived topoisomerase I inhibitor | Advanced NSCLC (1 L) | Promising antitumor activity in phase 2 | [ 72 ] |
| Datopotamab deruxtecan (Dato-DXd) | TROP2 | DXd topoisomerase I inhibitor | Early-stage breast cancer | High pCR rates in high-risk subtypes (I-SPY2.2) | [ 73 , 74 ] |
| Datopotamab deruxtecan (Dato-DXd) | TROP2 | DXd topoisomerase I inhibitor | Pretreated advanced NSCLC | ORR 26.0%, median PFS 3.6 months; resistance linked to low TROP2 staining and DNA repair activation | [ 75 ] |
| IBI343 | CLDN18.2 | Exatecan topoisomerase I inhibitor | Advanced G/GEJ adenocarcinoma | Manageable safety; DLTs at highest dose level | [ 76 ] |
| SHR-A1904 | CLDN18.2 | Topoisomerase I inhibitor | CLDN18.2 + advanced G/GEJ cancer | Promising antitumor activity in phase 1 | [ 77 ] |
| CMG901 | CLDN18.2 | MMAE (microtubule inhibitor) | Advanced G/GEJ cancer | Encouraging efficacy and tolerable safety | [ 78 ] |
| YL201 | B7-H3 | Novel topoisomerase I inhibitor | Various solid tumors (ES-SCLC, NPC) | MTD established; early efficacy in ES-SCLC and NPC | [ 79 ] |
Bispecific antibodies in solid tumors: mechanisms and clinical translation
EGFR-MET bispecific antibodies in non-small-cell lung cancer
The EGFR-MET bispecific antibody amivantamab has emerged as a transformative strategy in the management of EGFR-mutant non-small-cell lung cancer (NSCLC). By simultaneously targeting EGFR and MET, amivantamab inhibits ligand-induced receptor activation and promotes antibody-dependent cellular cytotoxicity, addressing both primary signaling and resistance mechanisms driven by MET amplification. The phase 1 CHRYSALIS trial demonstrated that amivantamab combined with the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib yielded a high overall response rate (ORR) and durable responses in patients whose disease had progressed on osimertinib, a population with historically limited options [ 38 ]. Preclinical work further supports this combination for uncommon EGFR mutations, as reviewed in [ 91 ]. These findings have propelled amivantamab-based regimens into the frontline setting, with ongoing trials evaluating its role in delaying resistance and improving long-term outcomes [ 92 ]. The broader clinical impact of targeting MET alterations, including MET exon 14 skipping mutations and acquired amplification, is also being explored with MET-directed antibody-drug conjugates and bispecific antibodies, underscoring the evolving therapeutic landscape for NSCLC [ 93 ].
PD-1/CTLA-4 bispecific antibodies in gastric cancer and melanoma
Dual checkpoint blockade targeting PD-1 and CTLA-4 has been a cornerstone of immunotherapy, but the combination of separate monoclonal antibodies often increases toxicity. Bispecific antibodies like cadonilimab aim to deliver synergistic activity with a potentially improved safety profile. In HER2-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, the phase 1b/2 COMPASSION-04 trial established the safety and preliminary efficacy of cadonilimab plus chemotherapy as first-line treatment, with an ORR that compared favorably to historical controls [ 94 ]. A subsequent randomized phase 3 trial confirmed that cadonilimab plus chemotherapy significantly improved survival outcomes, including in patients with low PD-L1 expression, a subgroup that often derives less benefit from PD-1 inhibitor monotherapy [ 41 ]. In the neoadjuvant setting for locally advanced G/GEJ adenocarcinoma, cadonilimab combined with FLOT chemotherapy achieved a pathological complete response rate of 26.8%, suggesting that dual checkpoint blockade can enhance tumor regression before surgery [ 95 ]. Beyond gastric cancer, the concept of dual PD-1/CTLA-4 blockade is being tested in other solid tumors. In melanoma, the randomized phase 1b/2 Morpheus-Melanoma trial evaluated tobemstomig, a PD-1/LAG-3 bispecific antibody, against nivolumab plus ipilimumab, demonstrating similar pathological response rates (80.0% vs. 77.3%) with a potentially differentiated safety profile [ 96 ]. These data highlight the potential of bispecific antibodies to simplify combination immunotherapy while maintaining or improving efficacy.
HER2-targeted bispecific antibodies in biliary tract and breast cancers
Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, has shown significant clinical activity in HER2-amplified biliary tract cancer (BTC). The pivotal phase 2b HERIZON-BTC-01 trial enrolled patients with previously treated, HER2-amplified BTC and reported a confirmed ORR of 41.3% with a median duration of response of 12.9 months, leading to regulatory interest in this underserved population [ 43 ]. The unique biparatopic binding of zanidatamab is thought to enhance receptor clustering and internalization, providing a mechanistic advantage over trastuzumab. In breast cancer, zanidatamab is being explored in combination with CDK4/6 inhibitors and endocrine therapy for hormone receptor-positive, HER2-positive metastatic disease, with early-phase results showing promising antitumor activity and a manageable safety profile [ 97 ]. The first-in-human phase 1 study of zanidatamab across multiple HER2-expressing solid tumors confirmed its tolerability and broad antitumor activity, supporting further development in HER2-driven cancers beyond breast and gastric indications [ 42 ].
DLL3-targeted bispecific T-cell engagers in small-cell lung cancer
Small-cell lung cancer (SCLC) remains an aggressive malignancy with limited therapeutic options. Delta-like ligand 3 (DLL3) is an attractive target due to its high surface expression on SCLC cells and minimal normal tissue expression. Tarlatamab, a DLL3-directed bispecific T-cell engager (BiTE), has demonstrated compelling clinical activity in heavily pretreated SCLC. In the phase 1 DeLLphi-300 trial, tarlatamab induced durable responses, leading to its accelerated approval in the United States for patients with previously treated SCLC [ 98 ]. Building on this success, the phase 1b DeLLphi-303 study evaluated tarlatamab in combination with PD-L1 inhibitors as first-line maintenance therapy after chemo-immunotherapy for extensive-stage SCLC, showing a manageable safety profile and encouraging preliminary activity, suggesting that DLL3-targeted immunotherapy can be safely integrated into earlier treatment lines [ 46 ]. The development of tarlatamab represents a paradigm shift in SCLC, a disease that has historically been refractory to immunotherapy, and has spurred interest in next-generation DLL3-targeted approaches, including antibody-drug conjugates and chimeric antigen receptor T cells [ 99 , 100 ].
Emerging bispecific antibodies and novel targets
The clinical pipeline of bispecific antibodies in solid tumors is rapidly expanding beyond these established targets. SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, has shown promising efficacy in a proof-of-concept phase 2 trial for unresectable stage III NSCLC, where neoadjuvant SHR-1701 with chemotherapy enabled a quarter of patients to undergo surgery with high rates of major pathological response [ 101 ]. The first-in-class EGFR-HER3 bispecific antibody-drug conjugate BL-B01D1 has demonstrated encouraging antitumor activity in a phase 1 trial across multiple solid tumor types, including NSCLC and esophageal squamous cell carcinoma, highlighting the potential of bispecific targeting to deliver cytotoxic payloads more precisely [ 87 , 88 ]. Additionally, T-cell receptor-based bispecifics like tebentafusp have shown clinical benefit in metastatic uveal melanoma, a tumor type resistant to checkpoint inhibitors, by redirecting T cells to gp100-expressing melanoma cells and remodeling the tumor microenvironment [ 102 ]. These examples illustrate the diversity of bispecific formats and mechanisms being deployed to overcome resistance and target historically intractable solid tumors.
The clinical translation of bispecific antibodies in solid tumors has yielded some of the most striking recent advances in oncology, particularly in settings where conventional therapies have failed. The success of amivantamab in EGFR-mutant NSCLC and tarlatamab in SCLC demonstrates that bispecific antibodies can effectively address resistance mechanisms and target lineage-specific antigens, respectively, achieving meaningful clinical benefit in heavily pretreated populations. However, the field faces several critical uncertainties. First, the optimal sequencing and combination of bispecific antibodies with existing standards—including TKIs, chemotherapy, and immune checkpoint inhibitors—remain poorly defined, and the risk of overlapping toxicities, particularly cytokine release syndrome and immune-related adverse events, necessitates careful dose optimization. Second, while dual checkpoint blockade with bispecific antibodies like cadonilimab appears to improve outcomes in PD-L1-low gastric cancer, the magnitude of benefit over PD-1 inhibitor monotherapy or combination chemotherapy alone requires validation in larger randomized trials with mature survival data. Third, the durability of responses to bispecific T-cell engagers in solid tumors lags behind that seen in hematologic malignancies, likely due to the immunosuppressive tumor microenvironment and antigen heterogeneity; strategies to enhance T-cell fitness and prevent antigen escape are urgently needed. Finally, the development of predictive biomarkers for bispecific antibody therapy is in its infancy, and without reliable patient selection tools, the risk of exposing patients to ineffective but toxic treatments remains high. Despite these challenges, the rapid pace of innovation in bispecific antibody engineering and the growing number of clinical trials in early-line settings suggest that these agents will become integral components of solid tumor treatment paradigms in the near future.
CD20×CD3 bispecific antibodies and other T-Cell engagers in lymphoma
The therapeutic landscape for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) has been fundamentally reshaped by the advent of T-cell-engaging bispecific antibodies (bsAbs). These agents, which redirect host T cells to eliminate malignant B cells, have demonstrated remarkable efficacy and a manageable safety profile, offering an “off-the-shelf” alternative to chimeric antigen receptor (CAR) T-cell therapy. The most clinically advanced class targets CD20 on B cells and CD3 on T cells, with mosunetuzumab, epcoritamab, glofitamab, and odronextamab representing the leading agents in this space. (Table 3 )
Mosunetuzumab, a CD20×CD3 bispecific antibody, was the first in its class to receive regulatory approval for R/R follicular lymphoma (FL) based on a pivotal phase 2 study. In this trial, fixed-duration mosunetuzumab induced an overall response rate (ORR) of 80% and a complete response (CR) rate of 60% in heavily pretreated patients [ 19 ]. Long-term follow-up at a median of 37.4 months confirmed the durability of these responses, with a median duration of response of 35.9 months and a 30-month remission rate of 72.4% among complete responders [ 20 ]. The median overall survival was not reached, and the 36-month survival rate was 82.4%, underscoring the potential for prolonged disease control with a fixed-duration, chemotherapy-free approach. The safety profile was characterized by cytokine release syndrome (CRS), which was predominantly low-grade and manageable with step-up dosing and supportive care.
Epcoritamab, a subcutaneously administered CD20×CD3 bispecific antibody, has shown compelling activity in both aggressive and indolent lymphomas. In the EPCORE NHL-2 trial, epcoritamab combined with rituximab and lenalidomide (R2) for a fixed duration in R/R FL achieved an ORR of 96% and a CR rate of 88%, with high CR rates maintained even in high-risk subgroups such as those with primary refractory disease (90%) or progression within 24 months of first-line therapy (83%) [ 103 ]. In the transplant-ineligible R/R diffuse large B-cell lymphoma (DLBCL) setting, epcoritamab plus gemcitabine and oxaliplatin (GemOx) yielded an ORR of 52% and a CR rate of 31.5% in a phase 1b/2 study, with a median duration of response of 10.2 months [ 21 ]. These data highlight the potential of epcoritamab-based combinations to improve outcomes in populations with limited therapeutic options.
Glofitamab, a CD20×CD3 bispecific antibody with a novel 2:1 format, has demonstrated significant activity in aggressive lymphomas, particularly in the post-CAR T-cell setting. A phase 2 LYSA study evaluated glofitamab in patients with R/R DLBCL who had failed CAR T-cell therapy, reporting a median overall survival of 15.3 months and a complete metabolic response rate that met the primary endpoint [ 22 ]. Preclinical work has further shown that glofitamab combinations with polatuzumab vedotin or chemotherapy synergistically enhance antitumor efficacy, augment intratumoral T-cell infiltration, and reduce T-cell exhaustion, providing a rationale for ongoing frontline and second-line trials [ 104 ]. The addition of the CD19-4-1BBL co-stimulatory molecule englumafusp alfa to glofitamab in a phase 1 trial demonstrated a manageable safety profile and promising activity in R/R B-NHL, suggesting that co-stimulation may further potentiate T-cell engager efficacy [ 105 ].
Odronextamab, another CD20×CD3 bispecific antibody, has been evaluated in both CAR T-naive and CAR T-exposed populations. In the phase 2 ELM-2 trial, odronextamab monotherapy in R/R DLBCL after ≥ 2 prior lines achieved an ORR of 52.0% and a CR rate of 31.5%, with a median duration of CR of 17.9 months [ 106 ]. Importantly, in a prespecified post-CAR T-cell expansion cohort of the ELM-1 study, odronextamab demonstrated an ORR of 48.3% and a CR rate of 31.7% in patients progressing after CAR T-cell therapy, with a median duration of response of 14.8 months and a median overall survival of 10.9 months [ 107 ]. Responses were consistent across prior CAR T-cell products and time to relapse, establishing odronextamab as an effective salvage option in this high-risk population.
Beyond CD20×CD3 bispecific antibodies, other T-cell engagers and immunotherapeutic strategies are being explored in lymphoma. The CD30/CD16A innate immune cell engager AFM13, which recruits natural killer (NK) cells and macrophages to CD30-positive lymphoma cells, showed preliminary efficacy in combination with pembrolizumab in a phase 1b study for R/R Hodgkin lymphoma (HL), with a manageable safety profile [ 108 ]. Allogeneic NK cells pre-complexed with AFM13 have also demonstrated complete responses in R/R CD30 + lymphomas with minimal toxicity [ 109 , 110 ]. In classical HL, the antibody-drug conjugate brentuximab vedotin (BV) has been a cornerstone of therapy, and its combination with checkpoint inhibitors has been actively investigated. The randomized phase 2 E4412 study compared BV plus nivolumab with or without ipilimumab in R/R HL, reporting high CR rates of 64.7% and 70.3%, respectively, although the addition of ipilimumab did not significantly improve progression-free survival and was associated with increased grade 3 rash [ 111 ]. BV combined with nivolumab and chemotherapy (AN + AD) as frontline therapy for advanced-stage HL achieved a CR rate of 92% in early-stage disease and an ORR of 96% in advanced-stage disease, with a favorable safety profile [ 112 , 113 ]. For older patients unfit for conventional chemotherapy, BV with dacarbazine or nivolumab produced durable responses, with a median progression-free survival of 47.2 months for the BV-dacarbazine combination [ 114 ]. The phase 3 KEYNOTE-204 trial established pembrolizumab as superior to BV in terms of progression-free survival in R/R HL patients who had relapsed post-autologous stem cell transplantation or were ineligible for it, further solidifying the role of PD-1 blockade in this disease [ 115 ]. Long-term follow-up of the KEYNOTE-087 study confirmed a 2-year ORR of 71.9% with pembrolizumab in R/R HL, with particularly durable responses in patients who had not received prior BV [ 116 ].
The integration of T-cell engagers into earlier lines of therapy and in combination with other agents is a rapidly evolving area. In follicular lymphoma, the movement of bispecific antibodies into frontline and second-line settings is anticipated, with the goal of achieving deeper and more durable remissions while minimizing chemotherapy exposure [ 117 , 118 ]. In mantle cell lymphoma, bispecific antibodies are being explored as a strategy to overcome resistance to Bruton tyrosine kinase inhibitors, with early-phase trials showing promise [ 119 , 120 ]. The sequencing of bispecific antibodies with CAR T-cell therapy is a critical clinical question. A meta-analysis comparing CAR T-cell therapy and bispecific antibodies as third- or later-line therapy for R/R DLBCL found that CAR T-cell therapy was associated with a higher CR rate (51% vs. 36%), but bispecific antibodies remain an important option, particularly for patients who are not candidates for or who relapse after CAR T-cell therapy [ 14 ]. The emergence of biomarkers to guide patient selection is an area of active investigation, with baseline T-cell fitness, tumor antigen expression, and minimal residual disease dynamics correlating with response to CD20×CD3 bispecific antibodies [ 53 , 54 ]. Specifically, a higher frequency of CD8 + effector memory T cells and lower expression of exhaustion markers such as PD-1, TIM-3, and LAG-3 on intratumoral T cells have been associated with deeper and more durable responses, while early clearance of minimal residual disease below 10⁻⁴ by circulating tumor DNA analysis has emerged as a potential on-treatment predictor of long-term remission.
The toxicity profile of CD3-based T-cell engagers is dominated by CRS, which is generally low-grade and manageable with step-up dosing, premedication, and early intervention with tocilizumab and corticosteroids. A comprehensive meta-analysis of clinical trials confirmed that CRS is the most common adverse event, though grade ≥ 3 CRS is relatively infrequent with current mitigation strategies [ 121 ]. Immune effector cell-associated neurotoxicity syndrome (ICANS) is less frequent than with CAR T-cell therapy but requires vigilance. Infections, cytopenias, and hypogammaglobulinemia are additional concerns, necessitating appropriate prophylaxis and monitoring [ 47 , 122 ]. The favorable safety profile of these agents, particularly the low rate of severe CRS with subcutaneous administration and optimized step-up dosing, has facilitated their use in community settings and in older or frail patients [ 123 ].
The rapid expansion of T-cell engagers and bispecific antibodies in lymphoma represents a paradigm shift, but several uncertainties and methodological weaknesses persist. The most promising approaches appear to be the fixed-duration combinations, such as epcoritamab with R2 in FL, which achieve remarkably high CR rates and offer the possibility of treatment-free intervals, potentially altering the natural history of the disease. The activity of these agents in the post-CAR T-cell setting, as demonstrated by odronextamab and glofitamab, addresses a critical unmet need and provides a viable salvage strategy. However, the current evidence base is largely derived from single-arm phase 1/2 trials with relatively short follow-up, and cross-trial comparisons are confounded by differences in patient populations, prior therapies, and response criteria. The true comparative effectiveness of different CD20×CD3 bispecific antibodies and their optimal sequencing relative to CAR T-cell therapy remain undefined in the absence of randomized head-to-head trials. Furthermore, the durability of responses beyond three years is still being established, and the mechanisms of resistance—including antigen escape, T-cell exhaustion, and immunosuppressive tumor microenvironment dynamics—are incompletely understood. The development of validated predictive biomarkers is in its infancy, and without them, treatment selection will remain largely empirical. Finally, the generalizability of trial results to real-world populations, particularly older and frail patients, requires prospective validation. Addressing these gaps through randomized trials, longer follow-up, and translational correlative studies will be essential to fully realize the potential of T-cell engagers in lymphoma.
Table 3 Key CD20×CD3 bispecific antibodies in lymphoma and their clinical outcomes Agent Key trial / combination Patient population ORR / CR rate Citation Mosunetuzumab Pivotal phase 2 (fixed-duration) R/R FL ORR 80%, CR 60% [ 19 ] Mosunetuzumab Long-term follow-up (37.4 mo) R/R FL 30-mo remission 72.4% (CR) [ 20 ] Epcoritamab EPCORE NHL-2 (+ R2) R/R FL ORR 96%, CR 88% [ 103 ] Epcoritamab Phase 1b/2 (+ GemOx) Transplant-ineligible R/R DLBCL ORR 52%, CR 31.5% [ 21 ] Glofitamab Phase 2 LYSA (post-CAR T) R/R DLBCL Median OS 15.3 mo [ 22 ] Glofitamab Preclinical (+ pola/chemo) DLBCL models Enhanced T-cell infiltration [ 104 ] Glofitamab Phase 1 (+ englumafusp alfa) R/R B-NHL Promising activity [ 105 ] Odronextamab Phase 2 ELM-2 (monotherapy) R/R DLBCL (≥ 2 prior lines) ORR 52.0%, CR 31.5% [ 106 ] Odronextamab ELM-1 post-CAR T cohort Post-CAR T R/R DLBCL ORR 48.3%, CR 31.7% [ 107 ]
Table 3
Key CD20×CD3 bispecific antibodies in lymphoma and their clinical outcomes
| Agent | Key trial / combination | Patient population | ORR / CR rate | Citation |
| Mosunetuzumab | Pivotal phase 2 (fixed-duration) | R/R FL | ORR 80%, CR 60% | [ 19 ] |
| Mosunetuzumab | Long-term follow-up (37.4 mo) | R/R FL | 30-mo remission 72.4% (CR) | [ 20 ] |
| Epcoritamab | EPCORE NHL-2 (+ R2) | R/R FL | ORR 96%, CR 88% | [ 103 ] |
| Epcoritamab | Phase 1b/2 (+ GemOx) | Transplant-ineligible R/R DLBCL | ORR 52%, CR 31.5% | [ 21 ] |
| Glofitamab | Phase 2 LYSA (post-CAR T) | R/R DLBCL | Median OS 15.3 mo | [ 22 ] |
| Glofitamab | Preclinical (+ pola/chemo) | DLBCL models | Enhanced T-cell infiltration | [ 104 ] |
| Glofitamab | Phase 1 (+ englumafusp alfa) | R/R B-NHL | Promising activity | [ 105 ] |
| Odronextamab | Phase 2 ELM-2 (monotherapy) | R/R DLBCL (≥ 2 prior lines) | ORR 52.0%, CR 31.5% | [ 106 ] |
| Odronextamab | ELM-1 post-CAR T cohort | Post-CAR T R/R DLBCL | ORR 48.3%, CR 31.7% | [ 107 ] |
BCMA×CD3 bispecific antibodies
B-cell maturation antigen (BCMA) has emerged as a central target for T-cell redirecting therapies in multiple myeloma, given its near-universal expression on malignant plasma cells. Teclistamab, a BCMA×CD3 bispecific antibody, was the first to receive regulatory approval in this class for triple-class exposed relapsed/refractory multiple myeloma (R/RMM). In the pivotal phase 1/2 MajesTEC-1 study, teclistamab demonstrated an overall response rate (ORR) of 63% in heavily pretreated patients, with 39.4% achieving a complete response (CR) or better. Correlative analyses from this trial revealed that better clinical outcomes were associated with higher baseline peripheral T-cell counts, whereas a higher proportion of immunosuppressive regulatory T cells correlated with a lack of response, underscoring the importance of immune fitness [ 53 ]. The efficacy of teclistamab in patients with prior BCMA-directed therapy was further explored in a dedicated cohort of MajesTEC-1. Among 40 patients who had received a BCMA-targeted antibody-drug conjugate (ADC) or chimeric antigen receptor (CAR) T-cell therapy, the ORR was 52.5%, with 30.0% achieving CR or better and a median duration of response of 14.8 months, indicating that sequential BCMA-targeting is feasible [ 124 ]. Teclistamab is also being investigated in earlier lines of therapy. In the phase 2 MajesTEC-5 study, teclistamab combined with daratumumab and lenalidomide as induction in transplant-eligible newly diagnosed multiple myeloma (NDMM) yielded high rates of minimal residual disease (MRD) negativity, suggesting potential for deep responses in the frontline setting [ 125 ].
Elranatamab is another BCMA×CD3 bispecific antibody evaluated in the MagnetisMM-1 and MagnetisMM-3 trials. In the phase 2 MagnetisMM-3 trial, which enrolled patients without prior BCMA-directed therapy, elranatamab produced a confirmed ORR of 61.0% with 35.0% achieving ≥ CR. After six cycles, responding patients could switch to biweekly dosing, and 80% of those who switched maintained or improved their response for ≥ 6 months. The 15-month progression-free survival (PFS) rate was 50.9% [ 9 ]. In the phase 1 MagnetisMM-1 study, which included a more heavily pretreated population (90.9% triple-class refractory, 23.6% with prior BCMA-directed therapy), elranatamab showed consistent efficacy with no dose-limiting toxicities observed during dose escalation [ 10 ].
Alnuctamab, a bivalent 2 + 1 format BCMA×CD3 bispecific antibody, was evaluated in a first-in-human phase 1 study. Subcutaneous administration was selected due to a more favorable safety profile compared to intravenous dosing. Among 95 patients treated subcutaneously, the ORR was 58.9% at the recommended phase 2 dose of 30 mg. Cytokine release syndrome (CRS) occurred in 57.9% of patients but was exclusively grade 1/2, while grade 3/4 neutropenia was observed in 43.2% [ 126 ]. Pavurutamab, another BCMA×CD3 bispecific T-cell engager, was studied in a phase 1/1b trial. At the recommended phase 2 dose, CRS was reported in 74.4% of patients, and grade ≥ 3 infections occurred in 60 patients, highlighting the infection risk associated with this class [ 127 ].
Resistance to BCMA×CD3 bispecific antibodies is increasingly linked to an immunosuppressive tumor microenvironment. In relapsing patients, T cells frequently upregulate inhibitory receptors such as PD-1 and CTLA-4, which contribute to T-cell exhaustion and diminished anti-myeloma activity [ 128 ]. Concurrently, the bone marrow niche becomes enriched with suppressive cell populations, notably regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which secrete immunosuppressive cytokines including TGF-β and IL-10, further impairing effector T-cell function and fostering immune escape [ 128 ].
GPRC5D×CD3 bispecific antibodies
G protein-coupled receptor class C group 5 member D (GPRC5D) is a highly selective target in multiple myeloma with limited expression on normal tissues, making it an attractive alternative to BCMA. Talquetamab, a GPRC5D×CD3 bispecific antibody, has shown remarkable activity in heavily pretreated patients. In the phase 1b TRIMM-2 study, talquetamab combined with daratumumab demonstrated an overall response rate (ORR) of 71.4% in the 0.4 mg/kg weekly (QW) cohort (n = 14) and 82.4% in the 0.8 mg/kg every-other-week (Q2W) cohort (n = 51), supporting further development, with oral adverse events (dysgeusia, dry mouth) and skin/nail toxicities being characteristic on-target effects [ 12 ]. The unique toxicity profile of talquetamab, including dysgeusia and skin-related events, is distinct from the cytopenias and infections more commonly seen with BCMA-targeted agents.
Forimtamig is a novel GPRC5D-targeting T-cell bispecific antibody engineered with a 2 + 1 format, providing bivalent binding to GPRC5D. Preclinical characterization demonstrated that this bivalent binding confers higher affinity, more stable immunological synapses, and greater potency in tumor cell killing and T-cell activation compared to classical 1 + 1 formats. This design was motivated by the observation that GPRC5D antigen loss occurs more frequently than BCMA loss under therapeutic pressure, necessitating a more potent initial hit [ 129 ]. Clinical data for forimtamig are eagerly awaited to determine whether this enhanced format translates into improved durability of response.
A critical challenge with GPRC5D-targeted therapies is the emergence of antigenic escape. A comprehensive genomic, transcriptomic, and epigenomic analysis of clonal plasma cells from 21 patients relapsing after anti-GPRC5D T-cell engager therapy (talquetamab) revealed that 68.4% of relapsed cases exhibited antigenic drift (with primary refractory cases excluded from the denominator). Three distinct mutational mechanisms were identified: biallelic deletions at the GPRC5D locus; monoallelic deletion coupled with single-nucleotide variants or insertions/deletions on the remaining allele, which frequently disrupt conserved GPCR motifs critical for membrane trafficking and lead to endoplasmic reticulum trapping; and epigenetic silencing of the GPRC5D promoter or enhancer [ 51 ]. Notably, multiple subclones bearing distinct genomic alterations can co-emerge within individual patients, illustrating convergent evolutionary trajectories under therapeutic pressure [ 51 ]. These findings underscore the need for strategies to circumvent antigen escape, such as dual-antigen targeting.
FcRH5×CD3 bispecific antibodies
Fc receptor-homolog 5 (FcRH5) is a membrane protein ubiquitously expressed on myeloma cells, and cevostamab is a first-in-class FcRH5×CD3 bispecific antibody. In the phase 1 GO39775 trial, 324 heavily pretreated patients (median 6 prior lines; 89.5% triple-class refractory; prior BCMA-targeted therapy in a substantial proportion) received fixed-duration cevostamab with step-up dosing and once-every-3-weeks administration for up to 17 cycles. The safety profile was characterized by CRS, cytopenias, and infections, consistent with other T-cell engagers. Efficacy data from this trial demonstrated that FcRH5 is a viable target in R/RMM, including in patients with prior BCMA-directed therapy exposure [ 13 ].
Safety and management considerations
The safety profile of bispecific antibodies in multiple myeloma is dominated by CRS, cytopenias, infections, and hypogammaglobulinemia. A meta-analysis of clinical trials evaluating CD3-based T-cell engagers in cancer patients provided pooled incidence estimates for these adverse events, confirming that CRS is the most common toxicity, though grade ≥ 3 events are relatively infrequent with step-up dosing and subcutaneous administration. The European Myeloma Network has published consensus recommendations for the prevention and management of these toxicities, including premedication, step-up dosing, early use of tocilizumab and corticosteroids for CRS, and supportive measures for infections and cytopenias [ 47 ]. The International Myeloma Working Group has also provided comprehensive guidelines for the optimal use of T-cell-engaging bispecific antibodies in clinical practice, emphasizing the need for vigilant monitoring and multidisciplinary care [ 49 ]. (Fig. 1 )
Fig. 1 Safety and management considerations for bispecific antibodies (bsAbs) in multiple myeloma. The upper panel illustrates the mechanism of bsAbs and highlights key adverse events (AEs) including Cytokine Release Syndrome (CRS), cytopenias, infections, and hypogammaglobulinemia. The lower panel outlines comprehensive management and mitigation strategies, emphasizing prophylaxis, monitoring, adherence to European Myeloma Network (EMN) consensus guidelines, and targeted supportive care such as IVIG replacement and G-CSF. Illustrations were prepared using a Gemini-powered image-generation pipeline; the generated images were manually reviewed and edited by the authors
Resistance mechanisms
Resistance to bispecific antibodies in multiple myeloma is multifactorial. Antigen escape, as demonstrated for GPRC5D, is a major mechanism of acquired resistance [ 51 ]. T-cell exhaustion and an immunosuppressive tumor microenvironment also contribute to primary and secondary resistance. In the MajesTEC-1 study, baseline immune profiles correlated with response to teclistamab, with higher T-cell counts and lower regulatory T-cell proportions associated with better outcomes [ 53 ]. Dual-antigen-targeting strategies are being developed to address tumor heterogeneity and prevent antigen escape. Simultaneous targeting of BCMA and GPRC5D, for example, may improve efficacy and reduce the risk of relapse due to single-antigen loss [ 130 ]. A phase 1 trial of a BCMA/GPRC5D bispecific CAR T-cell therapy in patients with extramedullary disease demonstrated a 100% response rate, providing proof-of-concept for dual targeting in the T-cell engager space as well [ 131 ]. (Fig. 2 )
Fig. 2 Resistance mechanisms to bispecific antibodies (bsAbs) in multiple myeloma and future directions. The schematic illustrates three primary domains: (1) Acquired resistance driven by antigen escape, such as the loss or downregulation of GPRC5D; (2) Primary and secondary resistance mediated by T-cell exhaustion and an immunosuppressive tumor microenvironment (TME) involving Tregs, MDSCs, and inhibitory cytokines; and (3) The role of baseline immune profiling as predictive biomarkers for treatment response, alongside the potential of dual-antigen targeting bsAbs to overcome resistance. Illustrations were prepared using a Gemini-powered image-generation pipeline; the generated images were manually reviewed and edited by the authors
The evolving understanding of resistance mechanisms has also highlighted the role of the bone marrow microenvironment. Granulocytic myeloid-derived suppressor cells and other immunosuppressive populations are expanded in multiple myeloma and may contribute to resistance to T-cell-based therapies [ 132 ]. Furthermore, the progression from precursor states to symptomatic myeloma is characterized by an increasingly immunosuppressive microenvironment, which mirrors the mechanisms of immune escape that mediate resistance to T-cell-engaging therapies in advanced disease [ 133 ].
The clinical development of bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 has rapidly transformed the treatment landscape for relapsed/refractory multiple myeloma, offering off-the-shelf T-cell redirecting therapies with high response rates in heavily pretreated populations. The most promising aspect of this class is the ability to achieve deep and durable responses even in triple-class refractory disease, with teclistamab and elranatamab demonstrating CR rates exceeding 30% and median PFS approaching or exceeding one year in some studies. The emergence of subcutaneous formulations and fixed-duration treatment schedules further enhances the practicality and tolerability of these agents. However, real uncertainties persist regarding the optimal sequencing of these therapies relative to CAR T cells and ADCs, particularly given the growing evidence that prior BCMA-directed therapy attenuates but does not abrogate responses to subsequent BCMA-targeting bispecifics. The most critical gap is the lack of validated predictive biomarkers to guide patient selection; while baseline T-cell fitness and tumor antigen expression appear to influence outcomes, no clinically actionable assay exists to prospectively identify patients most likely to benefit. Furthermore, the mechanisms of resistance—particularly antigen escape through genetic and epigenetic alterations—are being elucidated at a rapid pace, yet therapeutic strategies to overcome or prevent resistance, such as dual-antigen targeting or combination approaches, remain in early clinical investigation. The toxicity profile, while manageable with current mitigation strategies, still poses a substantial burden, with high rates of grade ≥ 3 infections and cytopenias that may limit use in frail patients. The field must now move beyond single-arm phase 1/2 studies to randomized comparisons that define the place of bispecific antibodies within the broader therapeutic armamentarium, including their role in earlier lines of therapy and in combination with other agents such as daratumumab or immunomodulatory drugs.
CD19×CD3 bispecific antibodies and T-Cell engagers in leukemia
The CD19×CD3 bispecific T-cell engager (BiTE) blinatumomab has fundamentally altered the treatment paradigm for B-cell acute lymphoblastic leukemia (B-ALL) and has shown activity in chronic lymphocytic leukemia (CLL), particularly in its transformed state, Richter’s syndrome. Its mechanism of action—simultaneously binding CD3 on T cells and CD19 on B-lineage cells to form a cytolytic synapse—enables potent, polyclonal T-cell-mediated killing independent of major histocompatibility complex restriction or costimulation [ 134 ]. This section reviews the clinical development of blinatumomab across frontline, minimal residual disease (MRD)-positive, and relapsed/refractory (R/R) settings in ALL, as well as its application in CLL, and contextualizes these advances within the broader landscape of emerging T-cell engagers. Resistance to blinatumomab remains a critical challenge and is driven by several mechanisms, including CD19 antigen loss, lineage switch, T-cell exhaustion, and high disease burden. In clinical cohorts, CD19-negative escape has been reported in 10–30% of relapses following CD19-directed therapy, while lineage switch to a myeloid phenotype occurs less frequently and is strongly associated with KMT2A rearrangements, which drive epigenetic reprogramming and loss of B-lineage commitment [ 135 ].
Frontline therapy in acute lymphoblastic leukemia
The integration of blinatumomab into frontline regimens for adults with B-ALL represents one of the most impactful recent advances in leukemia therapy. Historically, adult ALL outcomes have lagged behind pediatric results, with high relapse rates despite intensive chemotherapy [ 136 ]. The GIMEMA LAL2317 phase 2 study investigated a chemotherapy-blinatumomab combination in 149 adults with newly diagnosed Philadelphia chromosome-negative (Ph-) B-ALL. Two cycles of blinatumomab were administered after chemotherapy cycles 3 and 6. The rate of molecular MRD negativity increased from 72% to 93% after the first blinatumomab cycle, with 73% of MRD-positive patients converting to MRD negativity. At a median follow-up of 38.1 months, median overall survival was not reached, and the 3-year overall survival rate was 80% [ 137 ]. This study demonstrated that early blinatumomab exposure can deepen molecular responses and improve long-term outcomes.
A similar approach was tested in the phase 2 GRAALL-2014/B-QUEST substudy, which enrolled 94 adults with high-risk Ph- B-ALL (defined by KMT2A rearrangement, IKZF1 deletion, or post-induction MRD ≥ 10⁻⁴). Patients received up to five 28-day cycles of blinatumomab during consolidation and maintenance. Compared to a historical control cohort of 90 high-risk patients treated with chemotherapy alone, blinatumomab consolidation was associated with improved relapse-free survival, supporting its role in mitigating the risk of relapse in genetically and molecularly defined high-risk subgroups [ 138 ]. A separate phase 2 trial in newly diagnosed Ph- BCP-ALL used a reduced-dose chemotherapy induction (idarubicin, vindesine, dexamethasone for 7 days) followed by 2 weeks of blinatumomab, achieving a composite complete remission rate of 94% with 86% achieving MRD negativity, highlighting the feasibility of de-escalating cytotoxic chemotherapy when immunotherapy is introduced early [ 139 ].
In Philadelphia chromosome-positive (Ph+) ALL, the combination of blinatumomab with potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) has yielded extraordinary results. A phase 2 trial of blinatumomab plus ponatinib in 76 newly diagnosed patients reported a complete molecular remission rate of 85% and an estimated 3-year overall survival of 88%, with only 13% of patients relapsing [ 140 ]. This chemotherapy-free regimen is reshaping the role of allogeneic stem cell transplantation in first remission. A comparative analysis of immune modulation between dasatinib plus blinatumomab and ponatinib plus blinatumomab revealed that dasatinib-based combinations induced greater lymphocyte expansion, increased NK and NK-T cell counts, and reduced regulatory T-cell frequencies, suggesting that the choice of TKI may differentially influence the immune milieu and potentially the durability of responses [ 141 ]. The MD Anderson experience over four decades has similarly shown that the integration of blinatumomab and inotuzumab ozogamicin into frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories in Ph- B-ALL, and to 90% with the blinatumomab-ponatinib regimen in Ph+ disease [ 142 ].
MRD-positive disease
MRD persistence after induction or consolidation chemotherapy is the strongest predictor of relapse in ALL. Blinatumomab was initially approved based on its ability to eradicate MRD in adults with B-ALL in hematologic complete remission. In a pivotal open-label, single-arm study, 78% of MRD-positive patients achieved a complete MRD response after one cycle of blinatumomab, and this molecular remission translated into prolonged relapse-free and overall survival [ 143 ]. This indication established a precedent for using T-cell engagers as a non-chemotherapeutic strategy to preempt overt relapse. The subsequent frontline studies described above have built on this principle, demonstrating that moving blinatumomab earlier in the treatment course—when disease burden is lower and T-cell fitness may be better preserved—can enhance MRD clearance rates and improve survival.
Relapsed/refractory acute lymphoblastic leukemia
In the R/R setting, blinatumomab was compared to standard chemotherapy in the phase 3 TOWER study, which demonstrated a significant overall survival benefit (median 7.7 months vs. 4.0 months) in adults with Ph- R/R B-ALL [ 144 ]. Health-related quality of life analyses from TOWER showed that blinatumomab-treated patients reported better global health status and physical functioning compared to those receiving chemotherapy, underscoring the tolerability advantages of immunotherapy in this heavily pretreated population [ 144 ]. Biomarker analyses from this trial identified that higher bone marrow blast percentage and lower platelet counts were associated with inferior responses, while T-cell expansion and lower regulatory T-cell frequencies correlated with better outcomes, providing early insights into predictors of response and resistance [ 145 ].
Resistance to blinatumomab remains a critical challenge, mediated by CD19 antigen loss, lineage switch to acute myeloid leukemia, T-cell exhaustion, and high disease burden [ 146 , 147 ]. The management of post-immunotherapy relapsed B-ALL requires a systematic approach, distinguishing between CD19-positive relapse, CD19-negative relapse, and lineage switch. For CD19-negative relapse, alternative antigen-targeted therapies such as the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin or CD22-directed chimeric antigen receptor (CAR) T cells are rational strategies [ 146 ]. Inotuzumab ozogamicin has demonstrated high response rates in R/R B-ALL and is being increasingly combined with blinatumomab in both frontline and salvage settings to target leukemic blasts through complementary mechanisms and potentially prevent antigen escape [ 148 ]. In pediatric R/R ALL, inotuzumab ozogamicin has also shown activity, with a phase 1 study establishing a recommended phase 2 dose and demonstrating responses in heavily pretreated children [ 149 ].
Chronic lymphocytic leukemia and Richter’s Syndrome
The role of blinatumomab in CLL has been explored primarily in the context of Richter’s syndrome, the transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Richter’s syndrome is characterized by frequent TP53 mutations, complex karyotypes, and poor responses to standard chemoimmunotherapy. A phase 2 study of high-dose blinatumomab (maximum 112 mcg/day) in 9 patients with Richter’s syndrome reported a durable complete response in one patient lasting over 1 year, with a manageable safety profile and no grade ≥ 3 cytokine release syndrome (CRS) [ 150 ]. While the overall response rate was modest, this study provided proof-of-concept that T-cell engagers can overcome TP53-mediated chemoresistance in this high-risk entity.
In the broader CLL landscape, the emergence of double-refractory disease (resistant to both covalent BTK inhibitors and BCL-2 inhibitors) has created an urgent need for T-cell-engaging therapies. CD19-directed CAR T-cell therapy (lisocabtagene maraleucel) and the noncovalent BTK inhibitor pirtobrutinib are currently standard options for double-refractory CLL, but bispecific antibodies targeting CD19 or CD20 are under active investigation in early-phase trials and have shown promising response rates in pretreated CLL [ 151 , 152 ]. These approaches aim to harness T-cell effector function in patients with compromised B-cell-targeted therapy options.
Emerging T-cell engagers and future directions
The success of blinatumomab has catalyzed the development of a new generation of T-cell-engaging bispecific antibodies with extended half-lives, subcutaneous administration, and alternative target antigens. In B-ALL, CD20×CD3 and CD22×CD3 bispecific antibodies are being explored to address CD19-negative escape. In CLL and B-cell lymphomas, CD20×CD3 bispecific antibodies such as mosunetuzumab, epcoritamab, and glofitamab have demonstrated high response rates and are moving into earlier lines of therapy [ 153 ]. The integration of these agents into frontline and MRD-driven strategies in ALL, and their combination with targeted therapies in CLL, represents the next frontier. Furthermore, the application of T-cell engagers is expanding beyond oncology; blinatumomab and the BCMA×CD3 engager teclistamab have shown efficacy in treatment-refractory autoimmune connective tissue diseases, suggesting a broader immunomodulatory potential [ 154 ].
The body of evidence supporting blinatumomab in B-ALL is robust and consistent across multiple clinical contexts, with the most transformative results emerging from its integration into frontline regimens. The ability of blinatumomab to deepen MRD responses and improve survival in both Ph- and Ph + ALL, particularly when combined with ponatinib in a chemotherapy-free manner, represents a paradigm shift that may reduce the need for allogeneic transplantation in first remission. However, several uncertainties persist. The durability of responses to chemotherapy-free regimens requires longer follow-up, and the optimal sequencing of blinatumomab with other immunotherapies—such as inotuzumab ozogamicin and CAR T cells—remains undefined. The real-world applicability of these intensive immunotherapy combinations in older or frail adults, who were underrepresented in many trials, is unclear. In CLL, the data for blinatumomab are limited to small, single-arm studies in Richter’s syndrome, and its role in non-transformed CLL is yet to be established, especially as CD20×CD3 bispecific antibodies with more convenient dosing schedules gain traction. A major methodological weakness across the field is the reliance on historical controls in many phase 2 studies, which limits the ability to definitively attribute survival improvements to blinatumomab rather than to broader improvements in supportive care or patient selection. Additionally, biomarkers of response and resistance—such as T-cell fitness, tumor microenvironment composition, and antigen escape mechanisms—are only beginning to be characterized prospectively, and their integration into clinical decision-making remains nascent. The most promising avenue for future investigation lies in rationally designed, biomarker-driven combinations that pair T-cell engagers with agents that enhance T-cell function, prevent antigen escape, or target parallel oncogenic pathways, with the goal of achieving durable remissions without the cumulative toxicities of multiagent chemotherapy.
Safety, resistance, and sequencing of antibody-based therapeutics
Resistance to antibody-based therapeutics, including monoclonal antibodies and ADCs, arises through diverse and often overlapping mechanisms. For monoclonal antibodies, resistance can involve downregulation or mutation of the target antigen, activation of bypass signaling pathways, or impairment of immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In the context of ADCs, resistance mechanisms are particularly multifaceted, reflecting the modular nature of these agents. Reduced antigen expression or internalization can limit drug delivery, while upregulation of drug efflux pumps, such as MDR1 (ABCB1) and BCRP (ABCG2), actively exports the released payload from tumor cells, diminishing intracellular drug accumulation. Additionally, activation of DNA damage repair pathways, including homologous recombination and base excision repair, can counteract the cytotoxic effects of DNA-damaging payloads, such as calicheamicin or topoisomerase inhibitors, thereby promoting tumor cell survival. These insights underscore the need for combination strategies that target these resistance nodes, such as co-administering efflux pump inhibitors or DNA repair inhibitors alongside ADCs.
Management of adverse events
The expanding use of antibody-based therapeutics, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor (CAR) T cells, has necessitated refined strategies for managing their unique toxicity profiles. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are hallmark adverse events of T-cell-engaging therapies. A consensus from the European Myeloma Network recommends premedication, step-up dosing, and the use of tocilizumab and corticosteroids for CRS, with anakinra considered for refractory cases [ 47 ]. A meta-analysis of CD3-based bsAbs confirmed that CRS is the most common treatment-related adverse event, though grade ≥ 3 events are relatively infrequent with current mitigation strategies [ 121 ]. For bsAbs in multiple myeloma, infections and cytopenias are additional major concerns, often requiring growth factor support and immunoglobulin monitoring [ 49 ]. The phase 1/2 BelaRd study in newly diagnosed, transplant-ineligible myeloma patients demonstrated that ocular adverse events from belantamab mafodotin can be managed using a hematologist-led vision-related anamnestic tool, reducing the burden of frequent ophthalmologic assessments [ 155 ]. In lymphoma, the combination of mosunetuzumab and polatuzumab vedotin showed a manageable safety profile, with CRS being mostly low-grade and occurring primarily in cycle 1 [ 23 ]. Patient-reported outcomes (PROs) from the POLARIX study in diffuse large B-cell lymphoma (DLBCL) revealed that clinician-reported adverse events often underestimate symptom burden, highlighting the importance of integrating PROs to fully characterize tolerability [ 156 ]. For solid tumors, the phase 1 trial of the SEZ6-targeting ADC ABBV-706 in small cell lung cancer reported anemia, fatigue, and neutropenia as the most common treatment-related adverse events, with a toxicity profile consistent with topoisomerase-1 inhibitor payloads [ 157 ]. Similarly, the TROP2-targeted ADC SHR-A1921 showed a low incidence of hematologic toxicities but notable stomatitis, underscoring the payload-dependent nature of ADC toxicities [ 55 ]. The management of infections remains critical, with updated ECIL guidelines providing specific antifungal prophylaxis recommendations for patients with hematological malignancies receiving novel immunotherapies [ 158 ].
Mechanisms of resistance
Resistance mechanisms to antibody-based therapies are extensively detailed in the disease-specific sections of this review. Briefly, antigen escape through genetic and epigenetic alterations is a dominant mechanism for T-cell engagers, as exemplified by GPRC5D loss in multiple myeloma (see GPRC5D×CD3 section) and CD19-negative relapse in B-ALL (see CD19×CD3 section). T-cell exhaustion, characterized by upregulation of inhibitory receptors and an immunosuppressive tumor microenvironment, is a shared barrier across BCMA- and CD20-directed bispecific antibodies (see BCMA×CD3 and CD20×CD3 sections). For ADCs, resistance arises from reduced antigen expression, payload efflux, and activation of DNA repair pathways, as discussed in the context of TROP2- and HER2-directed ADCs (see Expanding the ADC Landscape and HER2-Directed ADCs sections). Dual-antigen targeting and combination strategies are being developed to address these convergent resistance pathways.
Sequencing strategies
The optimal sequencing of ADCs, bsAbs, and CAR T cells across hematologic malignancies is an area of active investigation, guided by disease biology, prior treatment history, and overlapping toxicities. In relapsed/refractory multiple myeloma, the choice between BCMA-directed bsAbs and CAR T cells depends on patient fitness, disease tempo, and prior BCMA-targeted therapy exposure. Teclistamab has shown activity in patients with prior BCMA-directed ADC or CAR T-cell therapy, with an overall response rate of 52.5%, though responses were less durable than in BCMA-naïve patients [ 124 ]. The phase 3 DREAMM-7 trial demonstrated that belantamab mafodotin plus bortezomib and dexamethasone significantly improved progression-free and overall survival compared to daratumumab-based therapy in relapsed/refractory myeloma, supporting its use in earlier lines [ 159 ]. In DLBCL, a meta-analysis comparing CAR T cells and bsAbs as third- or later-line therapy found that CAR T cells achieved higher complete response rates (51% vs. 36%), but bsAbs offer an off-the-shelf option with a different toxicity profile [ 14 ]. For patients progressing after CAR T-cell therapy, the CD20×CD3 BsAb odronextamab demonstrated an overall response rate of 48.3% and a complete response rate of 31.7%, providing a viable salvage strategy [ 107 ]. In follicular lymphoma, fixed-duration mosunetuzumab achieved durable complete responses, with a 30-month remission rate of 72.4% in complete responders, suggesting that bsAbs may be positioned before or after CAR T cells depending on patient preference and disease characteristics [ 20 ]. The combination of epcoritamab with rituximab and lenalidomide in relapsed/refractory follicular lymphoma yielded a complete response rate of 88%, indicating that BsAb-based combinations may further improve outcomes and potentially shift sequencing paradigms [ 103 ]. In Hodgkin lymphoma, the incorporation of brentuximab vedotin into frontline and salvage regimens has improved outcomes, with the combination of brentuximab vedotin and nivolumab as first salvage therapy achieving a 3-year progression-free survival of 77% in patients proceeding to autologous stem cell transplantation [ 26 ]. The phase 3 ECHELON-1 study established brentuximab vedotin with AVD as a frontline standard for advanced-stage classical Hodgkin lymphoma, with sustained progression-free survival benefit at 3 years [ 25 ]. For pediatric ALK+ anaplastic large cell lymphoma, the addition of brentuximab vedotin to chemotherapy resulted in a 2-year event-free survival of 79.1% without excess toxicity, demonstrating the feasibility of integrating ADCs into frontline pediatric regimens [ 160 ]. In B-ALL, the sequential use of blinatumomab and inotuzumab ozogamicin is being explored to deepen responses and prevent relapse, with chemotherapy-free regimens showing promising molecular remission rates [ 137 , 148 ]. The treatment of double-refractory chronic lymphocytic leukemia now includes noncovalent BTK inhibitors and CD19-directed CAR T cells, with bsAbs emerging as a potential option for patients who have exhausted targeted therapies [ 151 ].
The rapid expansion of antibody-based therapeutics has undeniably improved outcomes across hematologic malignancies, yet the evidence base for optimal sequencing remains largely empiric, derived from single-arm studies and subgroup analyses rather than prospective randomized comparisons. The most promising approaches involve dual-antigen targeting to prevent antigen escape and the integration of ADCs or bsAbs into earlier lines of therapy, as exemplified by the DREAMM-7 and ECHELON-1 trials. However, a major uncertainty is the lack of validated predictive biomarkers for ADC and BsAb efficacy, which hampers personalized sequencing. While T-cell fitness and antigen expression levels show some correlation with response, these are not yet clinically actionable. Furthermore, the management of overlapping toxicities, particularly when combining ADCs with immunotherapies, is poorly defined, and PRO data remain underutilized in toxicity assessment. Methodological weaknesses include the heterogeneity of clinical trial populations, the absence of contemporary control arms in many BsAb studies, and the limited follow-up for late-onset toxicities such as secondary malignancies. Addressing these gaps through biomarker-driven trials and real-world evidence will be essential to move beyond empirical sequencing toward truly rational, individualized treatment algorithms.
Future directions and emerging strategies
The clinical success of antibody-drug conjugates (ADCs) has catalyzed the development of next-generation formats designed to overcome intrinsic limitations such as on-target/off-tumor toxicity, heterogeneous antigen expression, and therapeutic resistance. Bispecific ADCs represent a prominent evolution, simultaneously targeting two distinct antigens or epitopes to enhance tumor selectivity and mitigate antigen escape. BL-B01D1, a first-in-class EGFR-HER3 bispecific ADC, has demonstrated promising clinical activity in a phase 1 trial across multiple solid tumor types, including those with EGFR-mutant non-small-cell lung cancer (NSCLC) [ 88 ]. Similarly, the bispecific antibody-drug conjugate targeting EGFR and HER3, BL-B01D1, has shown efficacy in metastatic esophageal squamous cell carcinoma [ 87 ], while zanidatamab, a bispecific antibody targeting two HER2 epitopes, has achieved regulatory progress in HER2-amplified biliary tract cancer [ 43 ]. These constructs exemplify how dual targeting can address tumor heterogeneity and broaden the therapeutic window.
Probody-drug conjugates (PDCs) offer an alternative strategy to improve tumor specificity by exploiting the unique protease milieu of the tumor microenvironment. These conditionally activated ADCs remain inert in systemic circulation and are preferentially activated by tumor-associated proteases, thereby reducing off-target toxicity. Key proteases exploited for this purpose include matrix metalloproteinases such as MMP-2 and MMP-9, as well as urokinase-type plasminogen activator (uPA), which are frequently overexpressed in the tumor microenvironment and can cleave engineered masking peptides to restore antigen-binding and payload activity selectively at the tumor site [ 161 ]. Preclinical studies have demonstrated that such conditionally activated constructs can achieve a substantially improved therapeutic index compared with their unmasked parental ADCs, with reduced on-target toxicity in normal tissues while maintaining antitumor efficacy [ 161 ]. This approach is particularly relevant for targets with broad normal tissue expression, where conventional ADCs face dose-limiting toxicities [ 89 ]. The clinical translation of PDCs is still in early phases, but preclinical data support their potential to widen the therapeutic index for validated but challenging targets.
Immune-stimulating antibody conjugates (ISACs) represent a paradigm shift from direct cytotoxicity to immune activation. By conjugating immune agonists, such as Toll-like receptor (TLR) agonists or STING agonists, to tumor-targeting antibodies, ISACs aim to convert immunologically “cold” tumors into “hot” ones, thereby potentiating antitumor immunity. This concept is being explored in combination with immune checkpoint inhibitors to overcome resistance in tumors with low immunogenicity [ 162 ]. Early clinical data with FAP-targeted 4-1BBL bispecific molecules, which provide tumor-localized co-stimulation, have shown manageable safety and signs of activity in microsatellite-stable colorectal cancer, a typically immunotherapy-resistant setting [ 163 ]. The integration of ISACs with T-cell redirecting bispecific antibodies or checkpoint blockade is a logical next step to achieve durable responses.
Combination therapies are central to the future of antibody-based therapeutics, with the goal of achieving synergistic antitumor activity while managing overlapping toxicities. The combination of ADCs with immune checkpoint inhibitors is particularly compelling, as ADC-induced immunogenic cell death can enhance anti-PD-1/PD-L1 efficacy. Mechanistically, ADC-mediated cytotoxicity triggers the release of damage-associated molecular patterns (DAMPs) such as ATP, high-mobility group box 1 (HMGB1), and calreticulin exposure on the tumor cell surface, which collectively promote dendritic cell maturation, antigen cross-presentation, and subsequent T-cell priming [ 164 ]. Preclinical models have demonstrated that this immunogenic cell death can synergize with immune checkpoint blockade, converting the tumor microenvironment from an immunosuppressive to an immune-active state and thereby augmenting antitumor responses [ 164 ]. The phase 1b/2 BEGONIA trial demonstrated that first-line durvalumab plus trastuzumab deruxtecan achieved high response rates in HER2-low, hormone receptor-negative breast cancer [ 165 ]. In urothelial carcinoma, the combination of enfortumab vedotin and pembrolizumab has become a new standard of care, significantly improving survival over chemotherapy [ 166 ]. The NeoCOAST-2 platform trial in resectable NSCLC explored novel perioperative combinations, including durvalumab with the TROP-2 ADC datopotamab deruxtecan, yielding a pathological complete response rate of 35.2% [ 167 ]. These examples underscore the potential of ADC-immunotherapy combinations to move into earlier lines of therapy and curative-intent settings.
Bispecific T-cell engagers (TCEs) continue to evolve with improved formats and novel targets. The approval of tarlatamab, a DLL3-targeted TCE, for small-cell lung cancer validates the potential of TCEs in solid tumors [ 98 ]. In hematologic malignancies, fixed-duration combinations such as epcoritamab with lenalidomide and rituximab are achieving deep and durable responses in relapsed/refractory follicular lymphoma [ 103 ]. The development of trispecific antibodies and TCEs with integrated co-stimulatory signals, such as englumafusp alfa (a CD19-4-1BBL fusion) combined with glofitamab, aims to enhance T-cell function and overcome exhaustion [ 105 ]. Furthermore, TCR-based bispecifics like tebentafusp and IMA401 are expanding the targetable antigen repertoire to include intracellular proteins presented by HLA, opening new possibilities for tumors with low mutational burden [ 102 , 168 ].
The evolving role of antibody-based therapeutics in precision oncology is increasingly defined by biomarker-driven patient selection and adaptive trial designs. While target antigen expression remains a primary determinant of ADC activity, emerging evidence indicates that response is also influenced by tumor-intrinsic factors such as DNA repair pathway activation and the immune microenvironment [ 75 , 169 ]. Spatial determinants of ADC efficacy, such as the distribution of HER2-strong-positive tumor cells, are being explored to refine patient selection [ 66 ]. The integration of circulating tumor DNA and molecular residual disease monitoring is poised to guide adaptive therapy with ADCs and bispecifics, enabling early intervention and personalized treatment duration [ 170 ]. As the field matures, the convergence of novel formats, expanded target space, and rational combinations will likely cement antibody-based therapeutics as cornerstones of precision oncology across a broad spectrum of malignancies.
The most promising direction in this rapidly evolving landscape is the convergence of ADCs with immunotherapy, particularly in early-stage disease settings where the potential for cure is highest. The pathological complete response rates observed with neoadjuvant ADC-immunotherapy combinations in breast and lung cancers suggest that these regimens may fundamentally alter treatment paradigms, potentially reducing the need for cytotoxic chemotherapy. However, the field faces substantial uncertainties. The development of next-generation formats such as PDCs, ISACs, and trispecific antibodies will require novel biomarker strategies—such as protease-activity signatures for PDC activation or immunogenicity prediction algorithms for multispecific constructs—to realize their full potential. Methodologically, the proliferation of bispecific and multispecific constructs has outpaced the development of robust preclinical models that can accurately predict clinical toxicity, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity. The optimal sequencing of ADCs, TCEs, and cellular therapies is largely empirical, and the long-term consequences of sequential antigen-directed therapies on tumor evolution and immune fitness are poorly understood. Finally, the economic and logistical challenges of delivering these complex biologics globally, especially in resource-limited settings, threaten to widen existing disparities in cancer outcomes. Addressing these gaps through biomarker-integrated clinical trials and real-world evidence generation will be essential to realize the full potential of next-generation antibody-based therapeutics.
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Author contributions
JL and YL conceived and designed the review. JL performed the literature search and drafted the manuscript. YL critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
Funding
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Data availability
No datasets were generated or analysed during the current study.
Declarations
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Competing interests
The authors declare no competing interests.
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