Thalidomide

100 percent of evaluable patients achieved minimal residual disease (MRD) negativity following induction therapy in updated results from the Phase 2 MajesTEC-5 study TORONTO, Sept. 19, 2025 /PRNewswire/ -- Johnson & Johnson (NYSE:JNJ) today announced that an investigational immune-based induction regimen with TECVAYLI® (teclistamab-cqyv) and DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) demonstrated meaningful clinical efficacy in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Forty-nine patients were treated across three treatment cohorts, with a steroid-sparing approach, including regimens of TECVAYLI® with DARZALEX FASPRO® and lenalidomide, with and without bortezomib.1 Overall response (≥partial response) was achieved by 100% of patients in all treatment arms following induction therapy.1 Of 46 MRD-evaluable patients with available samples after Cycle 3 and/or Cycle 6, 100% achieved MRD negativity by next-generation flow at 10-5 sensitivity threshold.1 By next-generation sequencing, all were MRD-negative at 10-6 after Cycle 6.1 Overall, 85.7% (42/49) of patients achieved a complete response or better (≥CR) and were MRD-negative at Cycle 6 (≤10⁻⁵).1 Additionally, 96% of patients successfully completed stem cell mobilization with a median total stem cell yield of 8.1x106/kg.1 "Multiple myeloma weakens the immune system over time, making it difficult to eliminate cancerous plasma cells," said Marc S. Raab, M.D., Heidelberg University Hospital, Germany.* "It's critical to treat patients with the most effective regimens in the newly diagnosed setting. TECVAYLI and DARZALEX FASPRO work synergistically to significantly reduce cancer cells – resulting in deep responses with potential for long term benefit." Data from the safety analysis reinforced the tolerability of the approach.1 The most common treatment-emergent adverse events (TEAEs) were hematologic, and Grade 3/4 infections occurred in 36.7% of patients.1 Serious TEAEs occurred in 53% (n=26) of patients.1 No TEAEs led to full study treatment discontinuation and no Grade 5 adverse events were observed.1 Additionally, no patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS).1 Cytokine release syndrome (CRS) was observed in 65% of patients (n=32) and were all Grade 1/2.1 "Exploring TECVAYLI, with its established use in later lines of treatment, and DARZALEX FASPRO, a foundational therapy across all lines, together helps us understand how this doublet immunotherapy can support patients across different stages of disease," said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine. "Importantly, immune-based therapies like TECVAYLI have the potential to improve patient outcomes with a manageable safety profile, particularly when used earlier in the treatment journey, with 100 percent of evaluable patients achieving MRD negativity. We continue to explore TECVAYLI in earlier lines of therapy and across difficult-to-treat populations." About MajesTEC-5 Study MajesTEC-5 (NCT05695508) is an ongoing, Phase 2 study evaluating the safety and efficacy of combination regimens including teclistamab and daratumumab in participants with newly diagnosed transplant eligible multiple myeloma. The MajesTEC-5 clinical trial is sponsored by the German-Speaking Myeloma Multicenter Group (GMMG) and Deutsche Studiengruppe Multiples Myelom (DSMM), and conducted in collaboration with Johnson & Johnson.2 About TECVAYLI® TECVAYLI® (teclistamab-cqyv) received approval from the U.S. FDA in October 2022 as an off-the-shelf (or ready-to-use) antibody that is administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.3 Since FDA approval, more than 15,900 patients have been treated worldwide with TECVAYLI®. The European Commission (EC) granted TECVAYLI® conditional marketing authorization (CMA) in August 2022 as monotherapy for the treatment of adult patients with RRMM who have received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody, and have demonstrated disease progression since the last therapy. In August 2023, the EC granted the approval of a Type II variation application for TECVAYLI®, providing the option for a reduced dosing frequency of 1.5 mg/kg every two weeks (Q2W) in patients who have achieved a complete response (CR) or better for a minimum of six months. TECVAYLI® is a first-in-class, bispecific T-cell engager antibody therapy that uses innovative science to activate the immune system by binding to the CD3 receptor expressed on the surface of T-cells and to the B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells. In February 2024, the U.S. FDA approved the supplemental Biologics License Application (sBLA) for TECVAYLI® for a reduced dosing frequency of 1.5 mg/kg every two weeks in patients with relapsed or refractory multiple myeloma who have achieved and maintained a CR or better for a minimum of six months. For more information, visit . About DARZALEX FASPRO® and DARZALEX® DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for ten indications in multiple myeloma, three of which are for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible. It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO® is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme's ENHANZE® drug delivery technology. DARZALEX® (daratumumab) received U.S. FDA approval in November 2015 and is approved in ten indications, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible. DARZALEX® is the first CD38-directed antibody approved to treat multiple myeloma. DARZALEX®-based regimens have been used in the treatment of more than 618,000 patients worldwide. In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. Since 2020, the National Comprehensive Cancer Network® (NCCN®) has recommended daratumumab-based combination regimens for the treatment of newly diagnosed multiple myeloma and relapsed and refractory multiple myeloma.† For newly diagnosed multiple myeloma in non-transplant candidates, the NCCN® guidelines recommend daratumumab in combination with lenalidomide and dexamethasone as a Category 1 preferred regimen; daratumumab in combination with bortezomib, melphalan, and prednisone as another recommended Category 1 regimen; and daratumumab in combination with bortezomib, cyclophosphamide, and prednisone as another recommended Category 2A regimen. For newly diagnosed multiple myeloma in transplant candidates, the NCCN® guidelines recommend daratumumab in combination with bortezomib, lenalidomide and dexamethasone as another recommended Category 2A regimen; daratumumab in combination with bortezomib, thalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; daratumumab in combination with carfilzomib, lenalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; and daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as a Category 2A regimen useful in certain circumstances. For maintenance in transplant candidates, the NCCN guidelines recommend daratumumab in combination with lenalidomide as useful in certain circumstances. In relapsed/refractory myeloma, four daratumumab regimens are listed as Category 1 preferred regimens for early relapses (1-3 prior therapies): daratumumab in combination with lenalidomide and dexamethasone; daratumumab in combination with bortezomib and dexamethasone; daratumumab in combination with carfilzomib and dexamethasone; and daratumumab in combination with pomalidomide and dexamethasone [after one prior therapy including lenalidomide and a proteasome inhibitor (PI)]. The NCCN® also recommends daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as another Category 2A regimen for early relapses (1-3 prior therapies) and as monotherapy as a Category 2A regimen useful in certain circumstances for early relapse patients after at least three prior therapies, including a PI and an immunomodulatory agent, or for patients who are double refractory to a PI and an immunomodulatory agent. For more information, visit . About Multiple Myeloma Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.4 In multiple myeloma, these plasma cells proliferate and spread rapidly and replace normal cells in the bone marrow with tumors.5 Multiple myeloma is the third most common blood cancer worldwide and remains an incurable disease.6 In 2024, it was estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people would die from the disease.7 People living with multiple myeloma have a 5-year survival rate of 59.8 percent.8 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.9,10 TECVAYLI® IMPORTANT SAFETY INFORMATION WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI®. Initiate treatment with TECVAYLI® step-up dosing schedule to reduce risk of CRS. Withhold TECVAYLI® until CRS resolves or permanently discontinue based on severity. Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI®. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment. Withhold TECVAYLI® until neurologic toxicity resolves or permanently discontinue based on severity. TECVAYLI® is available only through a restricted program called the TECVAYLI® and TALVEY® Risk Evaluation and Mitigation Strategy (REMS). INDICATION AND USAGE TECVAYLI® (teclistamab-cqyv) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). WARNINGS AND PRECAUTIONS Cytokine Release Syndrome - TECVAYLI® can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI® at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI®. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation). Initiate therapy according to TECVAYLI® step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI® accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI® based on severity. TECVAYLI® is available only through a restricted program under a REMS. Neurologic Toxicity including ICANS - TECVAYLI® can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI® at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI®. In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI® at the recommended dose. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI®. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or permanently discontinue TECVAYLI® based on severity per recommendations and consider further management per current practice guidelines. Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI® step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves. TECVAYLI® is available only through a restricted program under a REMS. TECVAYLI® and TALVEY® REMS - TECVAYLI® is available only through a restricted program under a REMS called the TECVAYLI® and TALVEY® REMS because of the risks of CRS and neurologic toxicity, including ICANS. Hepatotoxicity - TECVAYLI® can cause hepatotoxicity, including fatalities. In patients who received TECVAYLI® at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS. Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity. Infections - TECVAYLI® can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI® at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI® and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity. Monitor immunoglobulin levels during treatment with TECVAYLI® and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Neutropenia - TECVAYLI® can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI® at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients. Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines. Monitor patients with neutropenia for signs of infection. Withhold TECVAYLI® based on severity. Hypersensitivity and Other Administration Reactions - TECVAYLI® can cause both systemic administration-related and local injection-site reactions. Systemic Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients, with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity. Embryo-Fetal Toxicity - Based on its mechanism of action, TECVAYLI® may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI® and for 5 months after the last dose. ADVERSE REACTIONS The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets. Please read full Prescribing Information, including Boxed WARNING, for TECVAYLI®. DARZALEX® INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS DARZALEX ® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma: In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent CONTRAINDICATIONS DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation. WARNINGS AND PRECAUTIONS Infusion-Related Reactions DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX. Interference With Serological Testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®. Neutropenia and Thrombocytopenia DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets. Interference With Determination of Complete Response Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein. Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose. The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy. ADVERSE REACTIONS The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia. Please click here to see the full Prescribing Information. About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JNJInnovMed. Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Global Services, LLC and Janssen Scientific Affairs, LLC are Johnson & Johnson companies. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of TECVAYLI® (teclistamab-cqyv) and DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's most recent Annual Report on Form 10-K, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments. Footnotes * Marc S. Raab, M.D., Heidelberg University Hospital, Germany, has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work. 1 Raab, Marc, S., et al, Post-Induction Outcomes and Updated Minimal Residual Disease Analysis From GMMG-HD10/DSMM-XX (MajesTEC-5): a Study of Teclistamab-Based Induction Regimens in Newly Diagnosed Multiple Myeloma (NDMM). 2025 International Myeloma Society Annual Meeting. September 2025. 2 GMMG-HD10 / DSMM-XX / 64007957MMY2003, MajesTEC-5 (HD10/DSMMXX). . Accessed September 2025. 3 U.S. FDA Approves TECVAYLI® (teclistamab-cqyv), the First Bispecific T-cell Engager Antibody for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. . Accessed September 2025. 4 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-5672020;95(5):548-567. 5 National Cancer Institute. Plasma Cell Neoplasms. . Accessed September 2025. 6 City of Hope. Multiple Myeloma: Causes, Symptoms & Treatments. . Accessed September 2025. 7American Cancer Society. Key Statistics About Multiple Myeloma. . Accessed September 2025. 8 SEER Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. . Accessed September 2025. 9 American Cancer Society. What is Multiple Myeloma? . Accessed September 2025. 10 American Cancer Society. Multiple Myeloma Early Detection, Diagnosis, and Staging. . Accessed September 2025. SOURCE Johnson & Johnson WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

“ 点击蓝字 关注我们 董晓武 浙江大学药学院教授，药学系副主任，博士生导师，博士，浙江省杰出青年基金获得者。主要从事药物化学和化学生物学研究，致力于合理药物设计和新药发现，聚焦靶向蛋白降解、人工智能药物设计、药物重定位等技术及其在新型先导分子发现中的应用，擅长创新药物临床前研究注册申报，主导研发的多个候选药物获得化药1类新药临床试验批件，并进入Ⅰ、Ⅱ期临床研究，部分品种已实现成果转化。迄今，在Nucleic Acids Res, Adv Sci, J Med Chem, Brief Bioinform等国际著名刊物上发表论文100余篇，他引2000次，H指数25。授权国家发明专利20项，其中国际授权专利4项。 车金鑫 浙江大学药学院特聘研究员，博士生导师，博士，浙江省科协青年人才托举工程入选者。主要从事基于结构的合理药物设计和新药发现研究工作，聚焦靶向蛋白降解剂和优势结构重定位研究，成功发现了多个具有进一步开发价值的候选分子。以第一/通信作者在ActaPharmSinB,JMedChem,AdvSci,AdvMater等国际学术期刊上发表论文40余篇，授权专利3项，主持国家自然科学基金、浙江省“尖兵领雁+X”科技计划等项目 基于蛋白降解靶向嵌合体/免疫调节药物的双功能降解剂研究进展PPS  段海婷，李林洁，董晓武*，车金鑫**  （浙江大学药学院，浙江 杭州 310058） [摘要]：靶向蛋白降解技术突破传统小分子药物对“不可成药”靶点的局限，为肿瘤和神经退行性疾病等提供了新型干预策略。蛋白降解靶向嵌合体（proteolysistargetingchimera，PROTAC）和分子胶凭借其独特的泛素-蛋白酶体系统调控机制，成为目前极具成药前景的蛋白质降解手段。免疫调节药物（immunomodulatorydrug，IMiD）不仅可以用作E3泛素连接酶配体，其固有的分子胶特性还能诱导新底物的泛素化降解，形成独特的双重降解特性。通过整合PROTAC的精准靶向能力和分子胶降解剂的底物重编程特性，可设计开发PROTAC/IMiD双功能降解剂，其通过协同降解目标蛋白（proteinofinterest，POI）及新底物，实现多通路协同治疗效应。代表性分子如NX-2127和KT-413已在临床前及早期临床试验中被证实具有克服耐药性、增强疗效的独特潜力。随着对E3泛素连接酶的系统性挖掘及多靶点协同药理机制的深入解析，这类双功能降解剂使得部分“不可成药”蛋白被成功靶向，为克服复杂疾病耐药等临床难题提供了优势策略。综述了基于蛋白降解靶向嵌合体/免疫调节药物的双功能降解剂的研究进展。 1  蛋白降解靶向嵌合体和分子胶降解剂概述       靶向蛋白降解技术[1]作为近20年涌现的革命性治疗策略，以其独特的“事件驱动”作用机制，成功突破了传统小分子药物对“不可成药”靶点的治疗局限，为肿瘤、神经退行性疾病等重大疾病的治疗开辟了新途径。蛋白降解靶向嵌合体（proteolysistargetingchimera，PROTAC）[2-3]是一种具有突破性潜力的异双功能分子（见图1），其分子结构由3个关键功能域——E3泛素连接酶配体、目标蛋白（proteinofinterest，POI）配体和连接两者的连接子（linker）组成。PROTAC通过劫持细胞内源性蛋白降解系统——泛素-蛋白酶体系统（ubiquitin-proteasomesystem，UPS）实现对POI的被动靶向降解[4-5]。E3泛素连接酶作为该系统的底物识别核心组分，具有显著的组织特异性表达和降解底物偏好，因此不同E3泛素连接酶配体的选择直接影响PROTAC分子的降解效率和靶向特异性[6]。尽管人类基因组编码超过600种E3泛素连接酶[7]，但目前仅不到2%被应用于靶向蛋白降解领域，如CRBN（cereblon）和VHL（vonHippel-Lindau）等[3]。CRBN作为Cullin-RING连接酶4（CRL4）-CRBNE3泛素连接酶复合物的底物识别亚基[8]，其底物配体如沙利度胺（thalidomide）及其结构衍生物来那度胺（lenalidomide）、泊马度胺（pomalidomide）相对分子质量小，结构相对简单，具有良好的细胞渗透性和成药性。基于这些优势，CRBN已成为目前PROTAC技术中最广泛应用的E3泛素连接酶，能够有效靶向并降解多种传统意义上“不可成药”的蛋白靶点，包括转录因子和支架蛋白等。 早期的沙利度胺、泊马度胺和来那度胺因其对免疫细胞的调节作用，被称为免疫调节药物（immunomodulatorydrug，IMiD）[9]。2014年，2项发表于Science的重要研究首次揭示了来那度胺的分子作用机制，证实其可作为分子胶降解剂515（moleculargluedegrader，MGD）发挥功能[10-11]（见图1）。研究表明，来那度胺能够特异性结合CRBN-DDB1-CUL4AE3泛素连接酶复合物，诱导其构象变化并产生新的底物结合界面，从而选择性招募Ikaros家族锌指（Ikarosfamilyzincfinger，IKZF）1和IKZF3等C2H2型锌指蛋白作为新底物（neo-substrate）并降解[12]。CRBN这种独特的分子胶作用模式促使POI发生多聚泛素化修饰，进而通过蛋白酶体依赖的降解途径被有效清除，阐明了IMiD类药物在治疗多发性骨髓瘤中的分子机制。此外，G1到S相变1（G1toSphasetransition1，GSPT1）[13]、酪蛋白激酶1α（caseinkinase1α，CK1α）[14]和婆罗双树样转录因子4（spaltliketranscriptionfactor4，SALL4）[15]等越来越多的蛋白也被鉴定为CRBN分子胶的新底物。随着对CRBN分子胶的深入探索和结构改造，基于沙利度胺及其衍生物开发的针对分子胶底物更具选择性和活性的分子被称为CRBNE3泛素连接酶调节剂（CRBNE3ligase-modulatingdrug，CELMoD）[16]。这些分子在IMiD的接出结构上延伸出更有利于蛋白-蛋白相互作用（protein-proteininteraction，PPI）的结构片段，使其对特定底物蛋白具有更高的靶向性。 研究表明，基于CRBN的PROTAC分子可能展现出独特的双功能降解特性，即同时具备靶向降解POI和诱导新底物降解的能力（见图2）。这种双轨降解机制对血液系统恶性肿瘤等疾病表现出独特的治疗优势：一方面通过POI的特异性降解实现靶向治疗，另一方面通过分子胶降解新底物协同增强药效。虽然这种PROTAC/IMiD双功能降解剂研究仍然相对较少（见表1），但已有相关分子进入临床研究阶段。 2 广泛研究的分子胶降解剂的新底物 2.1  IZKF1/IKZF3 IKZF1与IKZF3为Ikaros家族锌指蛋白，在免疫调节和某些肿瘤的发生发展中发挥着重要作用[17-18]。Ikaros可以直接启动或抑制抑癌基因或致癌基因，从而调节肿瘤细胞的生存和增殖[19]。IKZF1/IKZF32还参与淋巴细胞的多项发育过程。在T细胞中，IKZF1/IKZF3参与白细胞介素-2（interleukin-2，IL-2）的直接调节，间接调控T细胞亚群的分化和功能[11]。同时IKZF1/IKZF3还影响B细胞的分化和增殖并参与B细胞抗原受体（B-cellreceptor，BCR）通路的信号转导[10]。IKZF1/IKZF3还通过影响干扰素调节因子4（interferonregulatoryfactor4，IRF4）和细胞-骨髓细胞瘤病毒癌基因（cellularmyelocytomatosisviraloncogene，c-Myc）的表达，致使多发性骨髓瘤的异常增殖[10-11]。分子胶来那度胺对IKZF1和IKZF3的有效降解，实现了对血液系统B细胞恶性肿瘤和多发性骨髓瘤的治疗。截至目前，已有CC-92480[20]、CC-220[21]、CC-99282[22]和CFT7455[23]4个IKZF1/IKZF3降解剂进入临床试验。 2.2GSPT1     是一种高度保守的真核翻译终止因子，通过结合真核释放因子1（eukaryoticreleasefactor1，eRF1）形成功能性复合物，特异性识别终止密码子，进而迫使新生肽链从核糖体上解离[24]。GSPT1的下调可导致不同肿瘤细胞关键蛋白的异常表达，抑制增殖或诱导细胞凋亡。2016年，Celgene公司报道了首个靶向GSPT1的分子胶CC-885，并解析了三元配合物的晶体结构，揭示了GSPT1和IZKF1/IZKF3在与CRBN结合中采用相似的结合模式[13]。除此之外，首个选择性降解GSPT1的分子胶降解剂CC-90009也曾进入Ⅰ期临床研究，用于AML的治疗[25]。此外，专注分子胶的MonteRosaTherapeutics公司开发的MRT-2359也正处于临床试验阶段，用于MYC驱动的实体瘤的治疗[26]。 2.3IKZF2     随着分子胶降解剂研究的深入，多项研究表明，通过对沙利度胺衍生物的“药效团手柄”进行特定的结构修饰，可实现对IMiD新底物的选择性调控[27]。IKZF2与IKZF1/IKZK3同为Ikaros家族锌指蛋白[28]，在调节性T细胞（regulatoryTcell，Treg）中，IKZF2的缺失会导致叉头盒蛋白P3（forkheadboxP3，FOXP3）的表达下调，进而削弱Treg的免疫抑制功能[29]。基于此，诺华（Novartis）公司成功开发出靶向IKZF2蛋白的特异性分子胶降解剂DKY709，其目前处于Ⅰ期临床研究阶段，用于实体瘤的治疗[30]。这不仅揭示了IKZF2在维持Treg抑制表型中的关键作用，也为开发靶向免疫调节通路的降解剂提供了重要的结构借鉴和经验参考。 2.4其他CRBN分子胶降解剂的新底物 CK1α是调控Wnt/β-连环蛋白通路（Wnt/β-cateninpathway）和DNA损伤应答的关键激酶[31]。研究表明，CK1α可被来那度胺招募，与CRBN形成蛋白互作界面并被降解。然而，沙利度胺和泊马度胺对CK1α的降解效率非常微弱，仅为来那度胺的10%~20%[14]。因此在分子胶降解剂开发中，针对CK1α的研究也相对较少。此外，SALL4作为维持胚胎干细胞多能性和调控原始生殖细胞分化的核心转录因子，其异常降解被证实是沙利度胺类药物致畸性的主要分子机制。沙利度胺及其类似物通过CRBN依赖性途径诱导SALL4的多聚泛素化及蛋白酶体降解，导致胚胎发育过程中关键基因网络的失调[15]。因此，在基于CRBN的分子胶设计中，需严格评估候选分子对SALL4的脱靶降解风险，以规避潜在的发育毒性。值得注意的是，CRBN介导的分子胶降解底物还包括肿瘤蛋白p63（tumorproteinp63，简称p63）[32]和含锌指和BTB域16（zincfingerandBTBdomaincontaining16，ZBTB16）[33]。这些蛋白的非预期降解可能引发严重的脱靶效应，如组织发育异常或免疫稳态失衡。因此，在分子胶降解剂的优化过程中，需通过结构修饰、底物选择性筛选及体内外毒性评估，系统性平衡治疗效能与安全性。 3 PROTAC/IMiD 双功能降解剂 3.1BTK-IKZF1/3双功能降解剂     BTK是BCR信号通路的核心调控因子，其异常活化与慢性淋巴细胞白血病（chroniclymphocyticleukemia，CLL）[34]和MCL[35]等B细胞恶性肿瘤密切相关。虽然伊布替尼（ibrutinib）等BTK抑制剂已应用于临床，但仍面临着耐药突变和非激酶依赖逃逸等挑战。相比而言，BTK靶向降解剂通过UPS彻底清除BTK蛋白，不仅能克服激酶域突变耐药，还可同时消除其激酶活性和支架功能，更有效地阻断BCR信号通路。这种双重作用机制为克服现有抑制剂局限性提供了新策略。 NX-2127是Nurix公司通过药物设计和结构优化得到的强效、选择性且口服生物利用度良好的BTK-IKZF1/3双功能降解剂[36]。这种多靶点协同降解机制在B细胞恶性肿瘤治疗中展现出显著的协同治疗效果。NX-2127有效降解野生型BTK和临床常见的C481S等耐药突变体，并有效抑制BCR和Toll样受体（Tolllikereceptor，TLR）信号通路的异常激活。而NX-2127介导的IKZF1/IKZF3降解可促进IL-2的分泌，进而增强T细胞受体（T-cellreceptor，TCR）信号传导，促进T细胞的活化和增殖，同时通过非BTK依赖途径调控TLR信号通路（见图3）。目前，NX-2127针对复发/难治性B细胞恶性肿瘤患者的Ⅰ期临床试验（NCT04830137）正在进行中[37]。初步临床药效学数据显示，该药物在CLL患者中可以实现持续、有效的BTK蛋白降解（＞80%），并且在79%的患者中也观察到正向的临床效益，验证了其良好的临床转化潜力。 哈佛医学院NathanaelS.Gray教授团队基于其自主开发的蛋白降解药物发现平台，采用系统性结构优化策略，通过对PROTAC的3个关键结构模块 进行筛选，成功开发出具有BTK和IKZF1/IKZF3双功能降解活性的先导化合物DD-03-171[38-39]。该分子在多种B细胞恶性肿瘤模型中实现长时间的BTK蛋白的持续性降解（降解率＞90%），且在100nmol·L-1浓度下可有效降解IKZF1和IKZF3蛋白。DD-03-171具有良好的药代动力学和药效学特性，在MCL细胞和异种移植模型中显示强效抗肿瘤活性。因此，DD-03-171不仅在恶性B细胞血液肿瘤中具有持久降解活性和有效抑制信号传导和抗增殖的作用，同时具有克服临床耐药性的优势，用以对抗常规疗法耐药的B细胞恶性肿瘤。 3.2BTK-GSPT1双功能降解剂 研究发现GSPT1可被分子胶类降解剂通过CRBN依赖性途径特异性降解，这一发现使其成为继IKZF1/IKZF3之后IMiD分子胶最具治疗潜力的降解靶点之一，也为血液系统恶性肿瘤提供了新的治疗策略。清华大学饶燏教授团队创新性地提出了一种协同靶向策略：将BTK降解剂和GSPT1分子胶融合，有望在DLBCL和AML等血液系统恶性肿瘤中实现协同治疗效果。基于这一理论构想，该团队成功设计并合成了新型双功能降解剂GBD-9[40]，其中E3配体在CRBN和GSPT1中间形成蛋白互作表面，在细胞内实现了BTK和GSPT1的双轨降解（见图4）。同时GBD-9在DLBCL和AML等多种血液瘤细胞中展现出显著的生物学效应。该分子再次验证了PROTAC/IMiD双功能降解剂的设计可行性，进一步拓展了靶向BTK在新适应证中的应用潜力。 3.3IRAK4-IKZF1/3双功能降解剂 IRAK4是TLR和白细胞介素-1受体（interleukin-1receptor，IL-1R）信号通路的关键调控因子[41]，其通过髓样分化因子88（myeloiddifferentiationprimaryresponseprotein88，MYD88）突变介导的组成性激活，促进活化B细胞样DLBCL（activatedB-cell-like-DLBCL，ABC-DLBCL）的发生发展。IRAK4兼具激酶活性和支架功能，因此靶向降解比单纯抑制更具治疗优势。研究发现，同时降解IRAK4和IKZF1/3不仅能阻断核因子κB（nuclearfactor-κB，NF-κB）信号[42]，还可通过下调IRF4和激活Ⅰ型干扰素（interferon，IFN）增强免疫应答[43]。 KT-413[44]是Kymera公司开发的一种新型的双功能降解剂，该分子不仅实现了对IRAK4激酶活性和支架功能的完全靶向降解，还通过E3端的分子胶降解活性实现了对IKZF1/IKZF3的有效降解。该化合物在分子水平上表现出显著的协同效应：IRAK4的降解有效阻断了MYD88突变介导的NF-κB信号通路异常激活，而IKZF1/IKZF3的降解则通过下调IRF4表达和激活Ⅰ型IFN通路，重塑了肿瘤微环境的免疫应答特征（见图5）。临床前研究数据显示，在ABCDLBCL的体外和体内模型中，KT-413展现出优于单靶点降解剂的抗肿瘤活性，并能有效克服传统小分子抑制剂常见的耐药性问题。基于这些临床前研究数据，KT-413已进入针对MYD88突变型B细胞恶性肿瘤的Ⅰ期临床试验（NCT05233033）[45]。虽然目前试验暂停，但其创新的IRAK4和IKZF1/IKZF3协同降解机制为难治性DLBCL提供了新的治疗策略。 3.4WDR5-IKZF1/3双功能降解剂     WDR5是赖氨酸甲基转移酶2A（lysinemethyltransferase2A，KMT2A）复合物的核心组分[46]，通过WD40结构域介导蛋白互作，在AML[47]和胰腺导管腺癌（pancreaticductaladenocarcinoma，PDAC）[48]等肿瘤中发挥关键调控作用。虽然靶向WDR5-MLL的小分子抑制剂在体外显示抗增殖活性，但因无法全面阻断WDR5的非经典功能和多蛋白互作网络，体内疗效受限。相较之下，靶向WDR5的PROTAC通过诱导蛋白完全降解，可同时消除其支架功能和复合物组装能力，有效克服了抑制剂的局限性。GangGregWang教授团队近期报道了一种新型靶向WDR5的PROTAC/IMiD双功能降解剂MS40[49]。该分子有效实现了对表观遗传调控因子WDR5和IMiD新底物IKZF1/IKZF3的选择性协同降解。MS40在原代MLL中展现出显著的细胞增殖抑制活性。在具有IKZF1/IKZF3高表达特征的MLL异种移植模型中，MS40的双轨降解表现出显著优于传统WDR5PPI抑制剂的肿瘤抑制活性。因此MS40通过同时靶向表观遗传调控和免疫调节通路，不仅验证了WDR5蛋白降解在表观遗传治疗中的可行性，也有望成为治疗MLL等难治性血液恶性肿瘤的新型治疗模式。 3.6AR-GSPT1双功能降解剂 AR作为核受体超家族成员，其配体依赖性转录激活功能在PC的发生发展中起核心驱动作用[53]。AR信号通路的异常激活可导致肿瘤细胞对雄激素剥夺治疗（androgendeprivationtherapy，ADT）的适应性逃逸，进而进展为去势抵抗性前列腺癌（castration-resistantprostatecancer，CRPC）[54]。尽管第1代和第2代AR拮抗剂在早期治疗中展现出显著疗效，但AR扩增或功能获得性点突变常引发肿瘤耐药，极大限制了临床获益。 秦冲教授团队基于计算化学辅助的理性药物设计策略，开发出创新型ARPROTAC/IMiD双功能降解剂BWA-6047[55]。该分子作为PROTAC靶向招募CRL4-CRBN复合物，有效地穿透了GSPT1和CRBN蛋白之间的结合界面腔，通过范德华力和氢键诱导GSPT1的招募和降解。同时BWA-6047诱导AR蛋白的泛素化，实现双轨协同降解（见图7）。在AR过表达且对恩扎卢胺（enzalutamide）耐药的22Rv1前列腺癌细胞系中，BWA-6047展现出强效增殖抑制活性（IC50=1.1nmol·L-1），Westernblot试验显示AR和GSPT1蛋白水平呈剂量依赖性下降（DC50分别为3.7和1.2nmol·L-1）。在LNCaP异种移植瘤模型中，BWA-6047以20mg·kg-1剂量口服给药显著抑制小鼠肿瘤的生长[肿瘤生长抑制率（tumorgrowthinhibitionvalue，TGI）达60%]。该研究不仅为CRPC提供了同时靶向AR信号通路和翻译终止调控的双重治疗策略，更通过结构-功能优化验证了PROTAC/IMiD双功能分子在克服耐药性及增强疗效方面的独特潜力。 3.7双功能降解剂的结构特征 PROTAC/IMiD双功能降解剂是一类结构复杂但设计巧妙的靶向蛋白降解分子，其核心结构特征体现在三个关键模块的协同整合。这类分子通常包含两个独立的蛋白结合域：一个针对POI（如BTK或IRAK4），另一个针对IMiD新底物（如IKZF1/3或GSPT1），但后者多数在度胺类结构基础上进行细微的调整，通过合理设计的连接子实现连接。双功能降解剂这种双重E3连接机制可协同增强泛素化效率，但这类分子的空间构象需要精确调控——POI结合域与E3配体之间的相对取向必须满足三元复合物形成的最小能量构象要求，这通常通过引入可旋转键或刚性芳香环来实现。以GBD-9为例，通过优化长度的烷基链连接，确保两个降解模块互不干扰。此外，双功能降解剂常引入极性基团（如四氢吡喃）改善溶解性，同时通过甲基化或氟化修饰（如WDR5降解剂中的三氟甲基）增强蛋白结合亲和力。这种模块化设计理念不仅拓展了降解剂的应用范围，更为克服肿瘤异质性和耐药性提供了结构基础。但由于目前双功能降解剂的开发案例较少，如何考量靶点的适用性和协同有效性需要更多经验积累。 4 结语与展望 靶向蛋白降解技术，尤其是PROTAC/IMiD双功能降解剂的开发，代表了药物研发领域的一次重大突破。通过巧妙结合PROTAC的靶向降解能力与IMiD的分子胶特性，这类双功能分子不仅能够高效清除传统“不可成药”靶点，还能通过协同降解多蛋白实现更广泛的治疗效应。NX-2127、KT-413和GBD-9等候选药物的成功案例，验证了该策略在克服耐药性、增强药效及拓展适应证方面的独特优势。目前，部分分子已进入临床试验阶段，初步数据显示出良好的治疗效果，为肿瘤及免疫性疾病的治疗开辟了新路径。 目前，PROTAC/IMiD设计已经从简单的双功能分子发展为包含多种创新策略的复合平台。例如，三价PROTAC能同时招募两种不同的E3泛素连接酶（如CRBN和VHL），显著提高了降解效率。PROTAC/IMiD已成功应用于多种以往被认为“不可成药”的靶点，包括转录因子、支架蛋白、调节蛋白和突变致癌蛋白等，这也为传统药物开发实现了靶点扩展。PROTAC/IMiD双功能降解剂还具有多功能调控的潜力，不仅能够同时影响POI的酶活性和非酶功能，同时针对与POI共同影响疾病进程的IMiD底物也可以消除其生物学功能，从而更全面地达到预期药效。随着对CRBN等E3泛素连接酶识别机制的深入理解，以及各种E3配体-连接子中间体库的建立，可以相信，PROTAC/IMiD双功能降解剂的研发周期和成本在未来有望进一步降低。 尽管PROTAC/IMiD技术前景广阔，但其发展仍面临诸多挑战，包括相对分子质量大导致的成药性差、潜在的脱靶毒性、E3泛素连接酶选择有限以及合成难度高等。这些限制因素促使研究人员不断探索新的技术方向和优化策略，以充分释放PROTAC/IMiD的治疗潜力。 [1] Hinterndorfer M, Spiteri V A, Ciulli A, et al. 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Rational design of dual degraders by incorporating molecular glue structural features into PROTAC degraders[J]. J Med Chem, 2025, 68(10): 10268–10298. 美编排版：金霆辉 感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第7期。 《药学进展》杂志由教育部主管、中国药科大学主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。 《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。 《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。 联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn； 邮箱：yxjz@163.com； 电话：025-83271227。 欢迎投稿、订阅！ 往期推荐 聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航 我知道你在看哟