Self‐Assembling Multi‐Antigen T Cell Hybridizers for Precision Immunotherapy of Multiple Myeloma

Advanced Healthcare Materials · 2025-08-01 · 3 citations

Abstract Bispecific T‐cell engagers show promise in treating multiple myeloma (MM), but challenges remain in adaptability and targeting flexibility. This paper presents a novel T‐cell based immunotherapy, M ulti‐ A ntigen TC ell H ybridizers (MATCH), a modular, self‐assembling T‐cell engager designed for versatile and patient‐specific cancer targeting. MATCH consists of two components: a B‐cell‐targeting Fab’ fragment conjugated to a 25‐base morpholino oligonucleotide (Fab’ B cell antigen ‐MORF1) and a T‐cell engaging anti‐CD3 Fab’ fragment conjugated to the complementary morpholino oligonucleotide (Fab’ CD3 ‐MORF2). Upon hybridization of MORF1 and MORF2, MATCH enables pre‐targeting of malignant cells followed by in situ post‐assembly of the bispecific complex, facilitating targeted T‐cell recruitment. To enhance antigen specificity based on MM patient expression profile, a panel of Fab’‐MORF1 conjugates targeting key MM surface markers (Fab’ BCMA ‐MORF1, Fab’ SLAMF7 ‐MORF1, Fab’ CD38 ‐MORF1) is developed, which pairs interchangeably with Fab’ CD3 ‐MORF2 for T‐cell engagement. MATCH effectively induces immune synapse formation and exhibits potent, antigen‐specific cytotoxicity across MM cells. Ex vivo validation in patient‐derived bone marrow samples confirms significant tumor cell depletion. Preliminary in vivo studies in humanized mouse model demonstrated effective cancer inhibition along with favorable pharmacokinetics and distribution profiles. These findings support MATCH as a flexible and customizable immunotherapy platform with strong translational potential for the treatment of MM.

CD38-targeted antibody-polymer drug conjugates for enhanced treatment of multiple myeloma

Biomaterials · 2025-06-04 · 8 citations

Multiple myeloma (MM) remains a formidable disease, especially in relapsed or refractory cases when there are limited treatment options. In this study, we introduce two polymer-antibody drug conjugates (pADCs), ISA-P-EPI (U6244-021) and DARA-P-EPI (U6244-031), which contain semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugate attached to CD38-targeting antibodies Isatuximab (ISA) and Daratumumab (DARA). These pADCs enhance therapeutic efficacy by combining the specificity of ISA and DARA with the cytotoxic potency of EPI while preserving antibody function. The EPI is linked to the HPMA polymer backbone via a tetrapeptide spacer cleavable by lysosomal enzymes, enabling drug release upon endocytosis within tumor cells. This design achieves a higher drug-to-antibody ratio than conventional ADCs for safer delivery of drug payload. In vitro studies demonstrate efficient binding, internalization, and cytotoxic efficacy of these pADCs in MM cell lines. Mechanistic investigations revealed significant therapeutic effects, including cell cycle arrest, immunogenic cell death, and preserved antibody-dependent cellular cytotoxicity (ADCC). In addition, pADCs were effective in 5 out of 8 primary samples, with their efficacy closely correlating with CD38 surface expression levels. To enhance therapeutic outcomes, we employed panobinostat to upregulate CD38 expression, which further improved pADC efficacy. In a preclinical NRG mouse model inoculated with MM.1S-luc cells, pADC treatment significantly delayed tumor progression and prolonged survival, with all treated mice remaining alive at the 100-day endpoint. These findings underscore the potential of CD38-targeted pADCs as a novel approach to combining chemotherapy with immunotherapy for MM treatment, warranting further investigation into their optimization and clinical application.

Polymer-based chemo-immunotherapy: Combining immunogenic cell death induction and PD-L1 blockade enhances antitumor immunity in melanoma

Journal of Controlled Release · 2025-09-02 · 3 citations

Melanoma remains a challenging malignancy despite the significant outcomes achieved with immune checkpoint inhibitor (ICI) monotherapy. Here, we investigated a polymer-based chemo-immunotherapy strategy combining KT-1, a backbone-degradable N -(2-hydroxypropyl)methacrylamide (HPMA) copolymer–epirubicin conjugate that induces immunogenic cell death (ICD), with MPPA, a multivalent HPMA copolymer–peptide antagonist of PD-L1 (PPA: (NYSKPTDRQYHF). In B16F10 melanoma, a 3-day dosing schedule significantly outperformed 7-day dosing. KT-1 monotherapy induced CD8 + T cell–mediated immunity through increased infiltration and upregulation of effector genes (Prf1, Gzmk, Eomes, Xcl1, Cxcl10), with depletion studies confirming CD8 + T cell dependence. Concurrent KT-1 + MPPA administration proved superior to sequential dosing. Single-cell RNA sequencing revealed that KT-1 promoted dendritic cell maturation and CD8 + T cell activation, while MPPA selectively reversed KT-1–induced PD-L1 upregulation on tumor cells. The combination enhanced dendritic cell activation, CD8 + T cell cytotoxicity, and reduced regulatory T cell immunosuppression. Importantly, MPPA did not induce autoimmune diabetes in NOD mice, in contrast to conventional anti–PD-L1 antibodies, and showed no observed immune-related adverse effects highlighting the safety. These findings support HPMA copolymer-based chemo-immunotherapy as a safer, effective alternative to traditional ICI regimens for treating immune-excluded tumors.

PD-L1 targeted antibody-polymer-Epirubicin conjugate prolongs survival in a preclinical murine model of advanced ovarian cancer

Journal of Controlled Release · 2025-04-04 · 7 citations

T cell activation contributed to a more effective antitumor response. Repeated dosing amplified immunomodulatory effects, leading to durable immunity. These results highlight U6244-051 as a next-generation pADC with high translational potential, offering enhanced efficacy and reduced on-target, off-tumor toxicity.

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer

Journal of Controlled Release · 2024-11-08 · 9 citations

Enhanced effect of autologous EVs delivering paclitaxel in pancreatic cancer

Journal of Controlled Release · 2022 · 80 citations

• Cancer research
• Chemistry
• Pharmacology

Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives

Current Oncology · 2021-11-26 · 22 citations

CCNs are a specific type of matricellular protein, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members, which exist only in vertebrates. The architecture of CCN proteins is multi-modular comprising four distinct modules. CCN Proteins achieve their primary functional activities by binding with several integrin7 receptors. The CCN family has been linked to cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, chondrogenesis, and wound healing, among other biological interactions. Breast cancer is the most commonly diagnosed cancer worldwide and CCN regulated breast cancer stands at the top. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. The pro-tumorigenic CCN1, CCN2, CCN3, and CCN4 may lead to human breast cancer, although the anti-tumorigenic actions of CCN5 and CCN6 are also present. Several studies have been conducted on CCN proteins and cancer in recent years. CCN1 and CCN3 have been shown to exhibit a dual nature of tumor inhibition and tumor suppression to some extent in quiet recent time. Pharmacological advances in treating breast cancer by targeting CCN proteins are also reported. In our study, we intend to provide an overview of these research works while keeping breast cancer in focus. This information may facilitate early diagnosis, early prognosis and the development of new therapeutic strategies.

CD5L as an Extracellular Vesicle-Derived Biomarker for Liquid Biopsy of Lung Cancer

Diagnostics · 2021 · 58 citations

• Chemistry
• Molecular biology
• Cancer research

Cancer screening and diagnosis can be achieved by analyzing specific molecules within serum-derived extracellular vesicles (EVs). This study sought to profile EV-derived proteins to identify potential lung cancer biomarkers. EVs were isolated from 80 serum samples from healthy individuals and cancer patients via polyethylene glycol (PEG)-based precipitation and immunoaffinity separation using antibodies against CD9, CD63, CD81, and EpCAM. Proteomic analysis was performed using 2-D gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The expression of proteins that were differentially upregulated in the EVs or tissue of lung cancer samples was validated by Western blotting. The area under the curve (AUC) was calculated to assess the predictability of each differentially expressed protein (DEP) for lung cancer. A total of 55 upregulated protein spots were selected, seven of which (CD5L, CLEC3B, ITIH4, SERFINF1, SAA4, SERFINC1, and C20ORF3) were found to be expressed at high levels in patient-derived EVs by Western blotting. Meanwhile, only the expression of EV CD5L correlated with that in cancer tissues. CD5L also demonstrated the highest AUC value (0.943) and was found to be the core regulator in a pathway related to cell dysfunction. Cumulatively, these results show that EV-derived CD5L may represent a potential biomarker-detected via a liquid biopsy-for the noninvasive diagnosis of lung cancer.

Exosome-based hybrid nanostructures for enhanced tumor targeting and hyperthermia therapy

Colloids and Surfaces B Biointerfaces · 2021 · 37 citations

• Nanotechnology
• Cancer research
• Chemistry

Forward-Looking Multimodal Endoscopic System Based on Optical Multispectral and High-Frequency Ultrasound Imaging Techniques for Tumor Detection

IEEE Transactions on Medical Imaging · 2020-10-21 · 8 citations

We developed a forward-looking (FL) multimodal endoscopic system that offers color, spectral classified, high-frequency ultrasound (HFUS) B-mode, and integrated backscattering coefficient (IBC) images for tumor detection in situ. Examination of tumor distributions from the surface of the colon to deeper inside is essential for determining a treatment plan of cancer. For example, the submucosal invasion depth of tumors in addition to the tumor distributions on the colon surface is used as an indicator of whether the endoscopic dissection would be operated. Thus, we devised the FL multimodal endoscopic system to offer information on the tumor distribution from the surface to deep tissue with high accuracy. This system was evaluated with bilayer gelatin phantoms which have different properties at each layer of the phantom in a lateral direction. After evaluating the system with phantoms, it was employed to characterize forty human colon tissues excised from cancer patients. The proposed system could allow us to obtain highly resolved chemical, anatomical, and macro-molecular information on excised colon tissues including tumors, thus enhancing the detection of tumor distributions from the surface to deep tissue. These results suggest that the FL multimodal endoscopic system could be an innovative screening instrument for quantitative tumor characterization.