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Dr. Ma is a physician-scientist with over 25 years of experience bridging medicine, academia and biotechnology. After earning his medical degree from Hunan Medical University, he built a career focused on translating scientific research into real-world patient solutions. His leadership in both clinical and research roles reflects a commitment to advancing regenerative medicine. Currently, as US Chief Medical Officer at Oricell Therapeutics, he drives innovation in cutting-edge multispecific antibody technology in cell therapies.
Through this article Hong Ma is pointing out how multispecific antibodies and antibody-drug conjugates are changing the way we treat cancer and other tough diseases. He shows how new technology is making these treatments smarter and safer, even though there are still challenges to overcome. Despite the hurdles, these therapies bring real hope for patients who didn’t have many options before.
Monoclonal antibodies have transformed the therapeutic landscape of oncology and autoimmune diseases over the past three decades. In recent years, the field has witnessed substantial innovation through the evolution of multispecific antibody (MsAb), including T-cell engagers (TCEs) and antibody drug conjugates (ADCs). These next-generation biologics are designed to enhance tumor selectivity, overcome resistance mechanisms and engage effector immune responses, representing a new frontier in precision immunotherapy.
Recent Drug Approvals and Clinical Progress
Multispecific Antibody Approvals
The MsAb landscape has expanded significantly, with several notable approvals in 2024-2025. The Antibody Society reports 21 antibody therapeutics granted first approvals in at least one country during 2024, including several bispecific antibodies: tarlatamab for small cell lung cancer, zanidatamab for HER2-positive cancers, zenocutuzumab and odronextamab. These approvals demonstrate the growing clinical validation of bispecific formats.
Trispecific antibodies are poised for their first FDA approval by 2027, with over 50 candidates currently in clinical trials. Notable examples include ISB 2001 (BCMA/CD38/ CD3), which showed stronger cancer-killing potency than bispecific comparators in multiple myeloma and CS2009 (PD-1/VEGF/CTLA-4), which entered global Phase I trials in 2025. Innovent's IBI3019 (EGFR/CDH17/CD16A) may have better clinical efficacy in colorectal cancer with reduced toxicity compared to existing therapy.
ADC Approvals and Pipeline
The ADC field has seen remarkable growth. At AACR 2025, Chinese companies presented many investigational ADCs, including Alphamab Oncology's JSKN021 (an EGFR/HER3 bispecific dual-payload ADC) and CStone Pharmaceuticals' CS5006 (a first-in-class ITGB4-targeting ADC).
Recent ADC approvals include sacituzumab tirumotecan in 2024, while 30 investigational ADCs had marketing applications under review or in pivotal studies as of December 2024, including datopotamab deruxtecan, telisotuzumab vedotin and trastuzumab rezetecan. Zymeworks presented promising data on ZW327, a novel Ly6E-targeting ADC with topoisomerase inhibitor payload showing robust activity in NSCLC and gastrointestinal cancers.
Technology Platforms and Engineering Advances
MsAb Platforms
Recent advances in MsAb engineering emphasize improved developability—achieving optimal stability, solubility, viscosity, specificity and pharmacokinetics to support clinical translation. Key platforms include Zymeworks’ Azymetric™ and EFECT™ technologies, enabling trispecific TCEs such as ZW209 (DLL3×CD3×CD28). CStone’s ADC platform supports biparatopic constructs like CS5005 targeting SSTR2, while NextPoint’s B7-H7/HHLA2-targeted platforms are designed for ADCs and TCEs with expanded therapeutic windows. Innovent’s integrated antibody platforms have yielded multispecific candidates such as IBI3014, a TROP2×PD-L1 bispecific ADC, highlighting the convergence of multispecificity and targeted payload delivery.
Engineering challenges include maintaining natural IgG-like properties while enabling multiple specificities. Approaches include disulfide engineering, framework optimization and computational design tools like AbDesign that recombine FV backbone fragments. The 2+1 format (e.g., Innovent's MUC16 TCE) has shown improved tumor cell binding with reduced off-target activity.
ADC Platform Innovations
Recent innovations in ADC platforms aim to enhance efficacy and minimize toxicity. Dual-payload ADCs like JSKN021 leverage complementary mechanisms by combining a topoisomerase I inhibitor and MMAE. Bispecific ADCs, such as IBI3014, simultaneously target TROP2 and PD-L1 to integrate cytotoxicity with immune checkpoint inhibition. Tumor-selective activation strategies, exemplified by ZL-6201’s TMALIN® linker technology, reduce off-target effects. Additionally, novel payloads like Zymeworks' camptothecin-based ZD06519 offer superior therapeutic profiles.
Beyond oncology, ImmunoGen is advancing a CD45- targeting ADC for a conditioning regimen in autoimmune disease patients undergoing hematopoietic stem cell transplantation. In infectious disease, pathogen-specific ADCs targeting Staphylococcus aureus are being developed to deliver antibiotics directly to infected tissues, aiming to overcome resistance and reduce systemic exposure. These approaches reflect the growing potential of ADCs as precision therapeutics beyond cancer.
Persistent Challenges
Despite notable advances, MsAb and ADC platforms face critical development challenges. MsAbs, particularly trispecific formats, involve complex manufacturing processes requiring precise assembly of multiple binding domains. Non-IgG formats often suffer from rapid clearance, necessitating frequent dosing, while novel scaffolds carry a heightened risk of immunogenicity. TCEs, such as NPX372, require meticulous dose escalation to mitigate cytokine release syndrome.
ADCs also present ongoing hurdles. Payload-related toxicities, especially hematologic effects, continue to limit dosing flexibility. Resistance mechanisms, such as antigen downregulation and drug efflux, reduce longterm efficacy. Furthermore, achieving an optimal balance between systemic linker stability and efficient intracellular drug release remains difficult. Combining ADCs with chemotherapy or immunotherapy is promising yet overlapping toxicities complicate treatment regimens.
Looking ahead, innovations in synthetic biology, protein engineering and systems immunology are reshaping the field. Strategies include targeting the tumor microenvironment using MsAbs directed at regulatory immune cells, in vivo selection platforms to optimize therapeutic candidates and designing personalized antibodies based on patient-specific neoantigens. Combinatorial approaches involving ADCs and MsAbs with immune checkpoint or kinase inhibitors are under clinical evaluation across multiple malignancies.
Conclusion
MsAbs and ADCs represent a dynamic and rapidly evolving class of therapeutic modalities, offering new hope for patients with refractory cancers and challenging noncancer diseases. While both classes have demonstrated transformative potential, their successful development requires ongoing innovation in molecular design, patient selection and clinical management. As the field matures, integrating real-world data, artificial intelligence and translational biomarkers will be instrumental in optimizing clinical outcomes and broadening therapeutic reach.
