Acquired haemophilia A (AHA) is an autoimmune bleeding disorder mediated by the production of autoantibody inhibitors against factor VIII (FVIII), resulting in a bleeding phenotype. The standard treatment of AHA includes immunosuppressive therapy for inhibitor eradication, haemostatic treatment with FVIII bypassing agents and treatment of underlying causes. Emicizumab is a bispecific monoclonal antibody that restores the function of missing activated FVIII by bridging FIXa and FX. Emicizumab is successfully used for prophylaxis of bleeding in congenital haemophilia A patients with or without FVIII inhibitors; however, it is not licensed for AHA treatment in the United Kingdom. We summarise our single-centre experience of the use of emicizumab for the treatment of AHA in 10 patients in the United Kingdom. Emicizumab was started at a dose of 3 mg/kg weekly with a change to fortnightly after the fourth dose. Eight patients received a combination of corticosteroids, emicizumab and rituximab; the remaining two, emicizumab and corticosteroids. In seven patients, emicizumab was stopped after achievement of an FVIII response and haemostasis following a median of 7 doses (3-53). In one patient, the treatment with emicizumab was complicated by the development of microangiopathic haemolytic anaemia. Three patients died, and in two of them, the death was associated with bleeding.

Lactate is a major byproduct of Chinese hamster ovary (CHO) cell metabolism, typically accumulating during the exponential growth phase and being consumed later during the production phase. Although commonly viewed as a waste product, recent studies suggest that lactate may play a broader role in cellular regulation. To investigate this, we developed a system to modulate intracellular lactate levels by co-expressing lactate oxidase (LOX) and catalase (CAT) in specific cellular compartments, including the cytosol, nucleus, and mitochondria. Using CHO cells secreting a bispecific antibody, this approach enabled assessment of how compartment-specific reduction of intracellular lactate influences cell performance. Reduction of nuclear lactate levels resulted in the most pronounced improvements, including approximately 40% higher viable cell density, 35%-40% increased protein titer, and reduced oxidative stress in fed-batch cultures. In contrast, reduction of mitochondrial lactate levels had minimal impact, indicating that the functional role of lactate is highly dependent on its subcellular localization. Further analysis demonstrated that intracellular lactate reduction was associated with decreased histone acetylation and histone lactylation, a recently described epigenetic modification linked to lactate metabolism. These epigenetic changes correlated with reduced markers of DNA damage and repair activity, suggesting improved genome stability. Overall, our findings indicate that lactate functions as more than a metabolic byproduct and may act as a regulatory metabolite influencing epigenetic state and cellular performance. Targeted modulation of intracellular lactate therefore represents a promising strategy to enhance productivity in CHO cell cultures.

Bispecific Antibodies for Glomerular Diseases: Are We Ready for Prime Time?

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction marked by fluctuating muscle weakness, driven by pathogenic antibodies targeting acetylcholine receptors, muscle-specific kinase, or lipoprotein receptor-related protein 4. Traditional treatments such as corticosteroids and immunosuppressants provide symptomatic relief but are limited by systemic toxicity and variable efficacy. Advances in immunology have led to targeted biologics that address specific disease mechanisms, such as B-cell depleting antibodies like rituximab and inebilizumab, complement inhibitors such as eculizumab, ravulizumab, and zilucoplan, and neonatal Fc receptor antagonists like efgartigimod and rozanolixizumab that lower pathogenic IgG levels. Emerging molecular and cellular therapies, including T-regulatory cell therapy, RNA-based modulation, and chimeric antigen receptor T-cell therapy approaches, seek to achieve durable immune tolerance rather than transient suppression. However, therapeutic response varies due to immunologic heterogeneity, long-term safety concerns, and limited global access. Future directions focus on precision medicine, biomarker-guided treatment, and AI-assisted disease monitoring, alongside next-generation therapeutics such as long-acting FcRn inhibitors (IMVT-1402), bispecific antibodies (gefurulimab), and oral small molecules (remibrutinib, iptacopan). Collectively, these developments mark a shift from generalized immunosuppression toward mechanism-based, patient-centered care aimed at restoring lasting immune balance and improving quality of life in MG. This narrative review discusses these aspects to comprehend the existing understanding and challenges.

This review examines anatomic and functional outcomes of intravitreal faricimab for treating polypoidal choroidal vasculopathy (PCV), a neovascular age-related macular degeneration subtype common in Asian populations. Faricimab is a bispecific antibody targeting both VEGF-A and Ang-2, potentially offering more durable effects than standard anti-VEGF monotherapy. A narrative review was conducted by searching PubMed, Embase, and Web of Science through July 2024. Keywords included faricimab, polypoidal choroidal vasculopathy, and anti-VEGF. Eligible studies comprised English-language, peer-reviewed human trials (prospective, retrospective, case series, and reports). Conference abstracts and non-peer-reviewed sources were excluded. In treatment-naïve patients, preliminary data suggest that faricimab may yield favorable results, though findings are largely derived from small retrospective studies. Functionally, a one-year study reported significant improvement in mean best-corrected visual acuity (BCVA), from 0.30±0.33 logMAR at baseline to 0.16±0.26 logMAR at final visit. However, some studies note visual gains may not be statistically significant during initial loading phase. Anatomically, high polyp regression rates are key findings, with one study reporting 61.1% rate after three monthly injections. High rates of dry macula (60-80%) and significant reductions in central foveal thickness (CFT) and central choroidal thickness (CCT) are consistently observed. For patients with suboptimal response to prior anti-VEGF therapies, switching to faricimab presents mixed picture. While a prospective cohort study found no significant average improvement in visual acuity for switched PCV eyes, a case report showed dramatic improvement from 20/100 to 20/60 after two injections in a ranibizumab-refractory case. Anatomically, switched patients show significant reduction in choroidal thickness and serous pigment epithelial detachments (PEDs). However, the presence of polypoidal lesions was identified as a negative predictive factor for successfully extending the treatment interval. Based on limited retrospective evidence, faricimab may represent a promising therapeutic candidate for PCV, with several studies reporting anatomical improvements. The dual mechanism of action targeting both VEGF-A and Ang-2 may help address certain pathological features of the disease; however, confirmation from larger prospective studies is needed.

Bispecific antibodies (BsAbs) have demonstrated high efficacy in relapsed/refractory multiple myeloma (MM). However, patients with impaired performance status and clinical frailty are underrepresented in pivotal trials, which typically restrict enrollment to ECOG 0–1. As a result, evidence guiding BsAb use in frail and elderly patients – who represent a substantial proportion of real-world MM populations – remains limited. In particular, the feasibility of BsAb therapy in patients with ECOG >1, the need for treatment adaptations, and the impact of supportive care strategies are insufficiently characterized. We conducted a single-center real-world analysis of consecutive frail and elderly MM patients with ECOG performance status (PS) >1 treated with BsAbs between 2024 and 2026. Frailty was defined pragmatically by age ≥75 years and/or ECOG PS ≥2. Patients received talquetamab or elranatamab according to institutional practice. All patients were CAR-T naïve, and a subset had prior BCMA exposure with belantamab mafodotin. Data collection included baseline clinical characteristics, treatment exposure, step-up delays and dose modifications, safety outcomes, and treatment response assessed according to standard clinical criteria. All patients received immunoglobulin replacement therapy. In addition, viral (including CMV) and fungal molecular surveillance was performed prior to treatment initiation and at each febrile episode. Analyses were descriptive, with exploratory subgroup evaluation of patients with ECOG PS 3. Nine patients were included; five received talquetamab and four elranatamab. Five patients (56%) belonged to a high-risk ECOG PS 3 subgroup. Step-up dose delays and/or dose modifications were frequently required, reflecting advanced age, comorbidities, and functional impairment. Overall response rate was 78% (7/9), with ≥VGPR achieved in 44% (4/9). Responses were observed across the ECOG >1 population, including within the high-risk ECOG PS 3 subgroup, despite frequent treatment adaptations. Treatment initiation was feasible in all patients, including those with advanced frailty and ECOG PS 3. No patients discontinued therapy during step-up dosing due to intolerance, and treatment exposure was maintained despite frequent dose adaptations. Dose delays and modifications were implemented primarily to mitigate toxicity risk rather than in response to severe adverse events. Cytokine release syndrome occurred in five patients and was predominantly low-grade. Immune effector cell-associated neurotoxicity syndrome was observed in one patient. One patient experienced a grade ≥3 infection. No unexpected toxicities, early treatment discontinuations due to toxicity, or treatment-related mortality were observed. In this real-world cohort of frail and elderly MM patients with ECOG >1, BsAb therapy demonstrated clinically meaningful efficacy with manageable toxicity when individualized dosing and proactive supportive care strategies were applied. Poor performance status alone should not automatically preclude BsAb therapy. These findings support the feasibility of BsAbs in frail populations traditionally excluded from clinical trials and highlight the need for prospective studies specifically addressing this high-risk group.

Tumor-derived exosomes are powerful mediators of cancer progression, influencing the tumor microenvironment (TME) to promote immune evasion, metastasis, and therapy resistance. B7-H3 (CD276), a member of the B7 immune checkpoint family, is gaining attention as a multifunctional promoter of tumor progression. In addition to its well-known expression on tumor and immune cells, B7-H3 is also enriched in exosomes, where it influences both extracellular vesicle production and signaling. This review examines how B7-H3 impacts exosome biology and contributes to tumor progression. We discuss the mechanisms of exosome biogenesis, including ESCRT-dependent and ESCRT-independent pathways. Emerging evidence indicates that B7-H3 enhances vesicular release, remodels cargo composition, and modulates recipient cell behavior. Mechanistically, B7-H3 activates pathways such as STAT3, PI3K, and lipid metabolism, thereby amplifying oncogenic signaling and promoting a pro-tumor TME. Clinically, B7-H3-enriched exosomes show promise as diagnostic, prognostic, and predictive biomarkers in colorectal, prostate, and non-small cell lung cancers. Additionally, we discuss strategies for therapeutically targeting exosomal B7-H3, including monoclonal and bispecific antibodies, CAR-T cells, and exosome inhibitors, as well as their potential synergy with immunotherapies. Overall, current evidence positions B7-H3 as a crucial link between checkpoint proteins and exosome-mediated cancer progression, offering new avenues for biomarker development and precision oncology.

CM512, a potentially novel IgG1-based bispecific antibody dual-targeting TSLP and IL-13, for the suppression of type 2 inflammation.

Recent studies have demonstrated that patients with hematological malignancies (HM) exhibit significantly impaired humoral immune responses after coronavirus disease 2019 (COVID-19) vaccination. Although booster doses and cellular immune responses have been increasingly studied, few analyses have concurrently evaluated both humoral and cellular immunity in patients receiving bendamustine, bispecific antibodies, or CAR-T therapies. We aimed to assess the humoral immunogenicity, T-cell immune response, and booster effect after COVID-19 vaccination in patients with B-cell lymphoma undergoing immunochemotherapy or novel agent treatment. Serum antibodies to the severe acute respiratory syndrome coronavirus 2 spike protein (S-IgG) were measured after the second and booster (third) mRNA vaccinations, and specific T-cell responses were measured using the enzyme-linked immunosorbent spot method. Forty-six of 114 patients (40%) acquired antibodies. Age<65years (odds ratio 8.99) and CD19≥50/μL (odds ratio 19.7) were independent predictors of response. To support the selection of this threshold, operating characteristic curve analysis was performed and confirmed CD19≥50/μL as a clinically meaningful discriminator despite a lower statistical cutoff. Even in some patients who did not develop antibodies, T-cell responses were observed (36% after two doses; 45.5% after the booster). The booster vaccine enhanced antibody (40% to 62.9%) and T-cell (47.2% to 57.6%) responses. This study provides confirmatory real-world evidence that CD19 recovery is a key determinant of humoral response, while vaccine-induced T-cell immunity may be preserved even in antibody-nonresponders, supporting continued vaccination efforts in this high-risk population.

Hemophilia is an inherited bleeding disorder caused by deficiencies in coagulation factor VIII (FVIII) or factor IX (FIX), leading to impaired thrombin generation and recurrent bleeding episodes. For decades, prophylactic factor replacement therapy has been the mainstay of hemophilia management; however, its limitations-including treatment burden, inhibitor development, and incomplete bleeding control-have required the development of alternative therapeutic strategies. Non-factor therapies represent a major paradigm shift in hemophilia care by restoring hemostatic balance through mechanisms independent of FVIII or FIX replacement. These approaches include bispecific antibodies that mimic FVIII cofactor activity and rebalancing strategies that enhance thrombin generation by inhibiting anticoagulant pathways such as tissue factor pathway inhibitor or antithrombin. Clinical studies have demonstrated that non-factor therapies provide stable and predictable prophylactic efficacy, significantly reduce bleeding rates, and improve quality of life in people with hemophilia A or B, irrespective of inhibitor status. Despite these advances, important challenges remain. Non-factor therapies modify physiological coagulation pathways and may be associated with thrombotic events due to imbalance between procoagulant and anticoagulant mechanisms, particularly for rebalancing agents. In addition, the lack of standardized laboratory assays for assessing global coagulation potential, uncertainties regarding combination therapy during breakthrough bleeding or surgery, and concerns about long-term safety and cost burden could limit optimal implementation. This review summarizes the mechanisms of action, clinical evidence, and safety considerations of currently available and emerging non-factor therapies for hemophilia. We also discuss unmet clinical needs, patient management considerations, and future perspectives aimed at optimizing the safe and sustainable use of non-factor therapies into routine hemophilia care.

Bispecific antibodies (bsAbs) can simultaneously target two distinct antigens, offering enhanced therapeutic efficacy compared to conventional antibodies. However, their complex manufacturing process, involving pairing of four distinct polypeptide chains (two heavy and two light chains), enhances the analytical challenges in quality control. Here, we applied top-down mass spectrometry using electron capture dissociation (ECD) on a novel timsOmni platform to characterize the bsAb LaC49 (AR4A/AR3C) and its monospecific precursors, IgG1-AR4A and IgG1-AR3C. This bsAb was developed to target different epitopes of the E1E2 envelope glycoprotein on the surface of hepatitis C virus (HCV). The bsAb was prepared via controlled Fab-arm exchange. Native mass spectrometry revealed that the sample contained the intended bsAb but also products that displayed substantial structural heterogeneity, including residual monospecific IgG1-AR4A and multiple other mass variants. ECD MS/MS analysis of the F(ab')2 of these products provided comprehensive sequence coverage of the CDR3 regions from all four polypeptide chains, generating clear sequence ladders potentially suitable for de novo sequencing. Important impurities could be identified that could not be characterized by MS1 (intact mass) analysis alone, including multiple (alternative) signal peptide cleavages in the AR4A antibody and partial reduction of a functionally important disulfide bridge in the CDR3 region of the AR3C heavy chain, likely induced during bsAb preparation. Our findings demonstrate that top-down MS/MS analysis is key for the molecular-level characterization of bsAb modifications, as standalone intact mass analysis proved insufficient to distinguish between closely related molecular variants (i.e., separated by only 0.04 Da). This study also emphasizes the need for comprehensive batch-to-batch quality control during bsAb production, as structural modifications can impact binding specificity, therapeutic efficacy, and safety. The timsOmni platform with ECD fragmentation provides a powerful novel analytical tool for ensuring consistent product quality in bispecific antibody manufacturing and for antibody sequencing applications.

Abstract Background The immunosuppressive nature of tumor microenvironment (TME) limits the efficacy of current immunotherapies. Bispecific antibodies (bsAbs) offer a promising strategy to overcome this challenge by enabling localized immune activation. Specifically, simultaneously targeting the "don't eat me" signal CD24 on tumor cells and the co-stimulatory receptor 4-1BB on immune cells may provide potent anti-tumor effects while mitigating the systemic toxicity typically associated with conventional 4-1BB agonists. Here, we present the preclinical evaluation of IBD0333, a novel bsAb targeting CD24 and 4-1BB. Methods The binding affinity of IBD0333 to CD24 and 4-1BB was evaluated, and its pharmacodynamic effects were assessed through multiple in vitro assays. Anti-tumor efficacy of IBD0333 was evaluated using C57BL/6J-h4-1BB humanized mouse models in vivo, while pharmacokinetic and safety profiles were further investigated in cynomolgus monkeys. Results IBD0333 exhibited high-binding affinity to both human and cynomolgus monkey CD24 and 4-1BB proteins. Its agonistic activity toward 4-1BB was strictly dependent on CD24, as evidenced by potent NF-κB activation and cytokine induction only in the presence of CD24-positive tumor cells. IBD0333 also demonstrated appropriate FcγR binding and no-detectable ADCC/CDC activity. In a syngeneic tumor model, complete tumor regression was achieved at doses of 1 mg/kg and 3 mg/kg. Furthermore, IBD0333 was well tolerated in cynomolgus monkeys with no observed immunotoxicity or hepatotoxicity, and the no-observed-adverse-effect level (NOAEL) following repeated administration was established as 120 mg/kg. Conclusion IBD0333 is a tumor-conditionally activated anti-CD24×4-1BB bsAb that demonstrates potent antitumor efficacy along with a favorable safety and pharmacokinetic profile. These findings support its further clinical development.

Abstract Purpose: The IgG1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks PD-1 and LAG-3 expressed on activated T cells. Patients and Methods: This first-in-human, open-label, phase 1 trial of tobemstomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with three tumor-specific cohorts, enrolling CPI‑experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI‑naïve patients with esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, MTD and/or recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and preliminary antitumor activity. Results: Thirty-five (dose-escalation) and 69 patients (expansion) were enrolled. Tobemstomig was well-tolerated up to the highest tested dose of 2100 mg Q2W. The MTD was not reached, and 2100 mg Q2W was established as the RDE. Tobemstomig exhibited linear pharmacokinetics across the studied dose range. Partial responses were achieved by 2/4 (600 mg) and 4/13 (2100 mg) patients during dose-escalation, 6/41 CPI‑experienced melanoma patients (ORR: 15%; 95%CI: 6.6, 26.9) and 1/8 CPI-naïve ESCC patients (ORR: 12.5%; 90%CI: 0.6, 47.1). Proof-of-mechanism was demonstrated in CPI-experienced melanoma patients based on increases in the amounts of CD8+ T cells, expansion of stem-like CD8+ T cells, and the acquisition of cytotoxic effector functions, with limited changes in the Treg compartment. Conclusions: Tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications. The encouraging antitumor activity associated with pharmacodynamic activity, and proof-of-mechanism in CPI-experienced melanoma patients, indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.

ABSTRACTNeovascularization is a major cause of blindness in various retinal diseases, and inflammation aggravates the pathological and clinical conditions of these diseases. VEGFA or ANG‐2 neutralizing antibodies have been used to block pathological neovascularization. In this work, the effects of intraocular administration of neutralizing antibodies against VEGFA, ANG‐2, or bispecific to these two factors on pathological findings were examined in the oxygen‐induced retinopathy (OIR) mouse model. At both postnatal day (P)17 and P19, anti‐VEGFA and ‐ANG‐2 administration suppressed neovascularization, and the bispecific antibody attenuated neovascularization more efficiently. However, oxygen‐induced vaso‐obliteration was not modified by these antibodies. Numbers of photoreceptor, amacrine, and bipolar cells were reduced in the OIR retina, and the antibodies reversed these changes. Microglia‐specific gene expression increased in the OIR retina, and administration of the antibodies reduced the IBA1‐positive area in the OIR retina, although these antibodies did not affect Iba1 gene expression. Labeled VEGFA and ANG‐2 were found to be co‐localized with microglia, suggesting that VEGFA and ANG‐2 affect microglia activation directly. Taken together, neutralizing antibody to VEGFA or ANG‐2 attenuated oxygen‐induced neovascularization and inflammation, and the bispecific antibody more efficiently suppressed some features than the single antibody to VEGFA or ANG‐2.

Advances in Current and Emerging Immunotherapies for Ovarian Cancer.

Treatment and survival outcomes for patients with follicular lymphoma and POD24: a systematic review and meta-analysis.

Cytomegalovirus reactivation in multiple myeloma patients receiving bispecific antibodies.

Abstract Background: IMV-M, a bispecific anti-MUC16×anti-DR5 antibody, previously showed potent MUC16-selective antitumor activity in vitro and in xenograft models without requiring secondary crosslinking. In a pilot non-human-primate study, repeated 10 and 20 mg/kg dosing produced no detectable toxicity. Here, we demonstrate that IMV-M induces clustering of death receptor 5 (DR5; TNFRSF10B) through a novel MUC16-dependent mechanism: assembly of multiple IMV-M molecules on a single MUC16 molecule. IMV-M also lacked cytotoxicity toward hepatic cell lines. Methods: Three bispecific antibodies sharing identical anti-DR5 arms were generated: Sofituzumab (h5A3)×Lexatumumab scFv, 11D10/DR5×Lexatumumab scFv, and (anti-fluorescein)×Lexatumumab scFv. Sofituzumab recognizes multiple tandem repeats within human MUC16, whereas 11D10 binds a single non-repetitive epitope. The anti-fluorescein construct, which does not bind human cells, served as a negative control. Binding to MUC16 was evaluated by (i) ELISA with shed MUC16 and (ii) flow cytometry using MUC16-positive cells. Cytotoxicity was assessed by CellTiter-Glo after 48h exposure. Results: IMV-M bound shed MUC16 ≈11-fold and cell-surface MUC16 ≈8-fold more strongly than 11D10/DR5 at saturation, while apparent affinities were similar. Only IMV-M induced cytotoxicity in MUC16-positive PK-59 cells, demonstrating that MUC16-mediated clustering of DR5 is required for apoptosis. In hepatocyte-derived HepG2 and Hep3B cells (MUC16-/DR5+), IMV-M showed no cytotoxicity, whereas MUC16+/DR5+ OVCAR-3 cells were highly sensitive across all concentrations. Secondary crosslinking did not elicit killing in MUC16-negative cells. These findings indicate a low risk of off-target hepatic toxicity, consistent with the benign safety profile of earlier anti-DR5 antibodies. Conclusions: Effective DR5 agonism by bispecific antibodies requires high-order receptor clustering. IMV-M achieves this through MUC16-mediated assembly of multiple antibody molecules on a single MUC16 molecule, enabling potent, tumor-selective apoptosis without hepatotoxicity. Citation Format: Iosif M. Gershteyn, Viktor Goldmakher. Tumor-selective regression through MUC16-guided DR5 (TNFRSF10B) clustering by the bispecific anti-MUC16×anti-DR5 antibody IMV-M™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3176.

Bispecific antibodies (BsAbs) that bind two distinct antigenic epitopes represent a new therapeutic paradigm. However, their clinical benefits and global regulatory status remain uncertain. In this cross-sectional analysis, BsAbs data from the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Chinese National Medical Products Administration (NMPA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were identified up to December 31, 2025. BsAb indications, supporting trials (pivotal and confirmatory), and regulatory approval statuses were analyzed. Clinical benefits based on improved efficacy endpoints, and approval time lags among agencies, were compared. Twenty BsAbs and 33 BsAb indications were identified. Of 33 indications, 27 were oncology and six were non-oncology. Among oncology indications, only six (6/27, 22.2%) demonstrated benefits with improvements in overall survival (OS) and/or quality of life (QoL). The remaining 21 (21/27, 77.8%) oncology BsAb indications showed benefits based on surrogate endpoints. All six non-oncology indications showed benefits based on true endpoints without surrogacy. Among the 38 supporting trials for oncology indications, the majority (36/38, 94.7%) were pivotal trials, while only two (2/38, 5.3%) were confirmatory trials. Most of these trials (32/38, 84.2%) recruited relapsed/refractory patients. Of 20 BsAbs, 12 received initial approval from the FDA, five from EMA, two from NMPA, and one from PMDA. FDA-approved BsAbs obtained EMA approvals with a median lag of 82.5 days, whereas approvals in China and Japan were delayed by a median of 602 and 455 days, respectively. Most oncology BsAb indications remain without OS or QoL benefits. The FDA approved the largest number of BsAbs. Regulatory approval time lags in NMPA and PMDA are substantially longer than those in EMA.

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody-drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities.