Icotrokinra

2025 Second-Quarter reported sales growth of 5.8% to $23.7 Billion with operational growth of 4.6%* and adjusted operational growth of 3.0%* 2025 Second-Quarter reflects earnings per share (EPS) of $2.29 and adjusted EPS of $2.77 Significant new product pipeline progress including approval of IMAAVY for generalized myasthenia gravis, priority review for TAR-200, data for CARVYKTI overall survival and progression-free benefits in multiple myeloma, and continuation of the clinical trial for a general surgery robotic system, OTTAVA Strong operational performance and favorable foreign exchange results in Company increasing full year estimated reported sales5 guidance at the midpoint by $2 billion dollars to 5.4% and full year EPS guidance by $0.25 to $10.85. Adjusted operational EPS increased to $10.68 at the midpoint. NEW BRUNSWICK, N.J.--(BUSINESS WIRE)-- Johnson & Johnson (NYSE: JNJ) today announced results for second-quarter 2025. “Today’s strong results reflect the depth and strength of Johnson & Johnson’s uniquely diversified business operating across both MedTech and Innovative Medicine,” said Joaquin Duato, Chairman and Chief Executive Officer, Johnson & Johnson. “Our portfolio and pipeline position us for elevated growth in the second half of the year, with game-changing approvals and submissions anticipated in areas like lung and bladder cancer, major depressive disorder, psoriasis, surgery and cardiovascular, which will extend and improve lives in transformative ways.” Overall financial results Q2 ($ in Millions, except EPS) 2025 2024 % Change Reported Sales $23,743 $22,447 5.8% Net Earnings $5,537 $4,686 18.2% EPS (diluted) $2.29 $1.93 18.7% Q2 Non-GAAP* ($ in Millions, except EPS) 2025 2024 % Change Operational Sales1,2 4.6% Adjusted Operational Sales1,3 3.0% Adjusted Net Earnings1,4 $6,699 $6,840 -2.1% Adjusted EPS (diluted)1,4 $2.77 $2.82 -1.8% Free Cash Flow6,7 ~$6,200 $7,507 1 Non-GAAP financial measure; refer to reconciliations of non-GAAP financial measures included in accompanying schedules 2 Excludes the impact of translational currency 3 Excludes the net impact of acquisitions and divestitures and translational currency 4 Excludes intangible amortization expense and special items 5 Excludes COVID-19 Vaccine 6 Non-GAAP measure; defined as cash flow from operating activities, less additions to property, plant and equipment. Cash flow from operations, the most directly comparable GAAP financial measure, will be included in subsequent SEC filings. 7 Second-quarter YTD 2025 is estimated as of July 16, 2025 Regional sales results Q2 % Change ($ in Millions) 2025 2024 Reported Operational1,2 Currency Adjusted Operational1,3 U.S. $13,544 $12,569 7.8% 7.8 - 5.0 International 10,199 9,878 3.2 0.6 2.6 0.4 Worldwide $23,743 $22,447 5.8% 4.6 1.2 3.0 1 Non-GAAP financial measure; refer to reconciliations of non-GAAP financial measures included in accompanying schedules 2 Excludes the impact of translational currency 3 Excludes the net impact of acquisitions and divestitures and translational currency Segment sales results Q2 % Change ($ in Millions) 2025 2024 Reported Operational1,2 Currency Adjusted Operational1,3 Innovative Medicine $15,202 $14,490 4.9% 3.8 1.1 2.4 MedTech 8,541 7,957 7.3 6.1 1.2 4.1 Worldwide $23,743 $22,447 5.8% 4.6 1.2 3.0 1 Non-GAAP financial measure; refer to reconciliations of non-GAAP financial measures included in accompanying schedules 2 Excludes the impact of translational currency 3 Excludes the net impact of acquisitions and divestitures and translational currency Second-Quarter 2025 segment commentary: Operational sales* reflected below excludes the impact of translational currency. Innovative Medicine Innovative Medicine worldwide operational sales grew 3.8%*, with net acquisitions and divestitures positively impacting growth by 1.4%. Growth was primarily driven by DARZALEX, CARVYKTI, ERLEADA and RYBREVANT/LAZCLUZE in Oncology, TREMFYA and SIMPONI/SIMPONI ARIA in Immunology, and SPRAVATO in Neuroscience. Growth was partially offset by an approximate (1,170) basis points impact from STELARA in Immunology, and an approximate (130) basis points impact from COVID-19 in Infectious Diseases. MedTech MedTech worldwide operational sales grew 6.1%*, with net acquisitions and divestitures positively impacting growth by 2.0%. Growth was primarily driven by electrophysiology products and Abiomed in Cardiovascular, as well as wound closure products in General Surgery. Full-year 2025 guidance: Johnson & Johnson does not provide GAAP financial measures on a forward-looking basis because the company is unable to predict with reasonable certainty the ultimate outcome of legal proceedings, unusual gains and losses, acquisition-related expenses, and purchase accounting fair value adjustments without unreasonable effort. These items are uncertain, depend on various factors, and could be material to Johnson & Johnson's results computed in accordance with GAAP. ($ in Billions, except EPS) July 2025 April 2025 Adjusted Operational Sales1,2,5 Change vs. Prior Year / Mid-point 3.2% – 3.7% / 3.5% 2.0% – 3.0% / 2.5% Operational Sales2,5 / Mid-point Change vs. Prior Year / Mid-point $92.7B – $93.1B / $92.9B 4.5% – 5.0% / 4.8% $91.6B – $92.4B / $92.0B 3.3% – 4.3% / 3.8% Estimated Reported Sales3,5/ Mid-point Change vs. Prior Year / Mid-point $93.2B – $93.6B / $93.4B 5.1% – 5.6% / 5.4% $91.0B – $91.8B / $91.4B 2.6% – 3.6% / 3.1% Adjusted Operational EPS (Diluted)2,4 / Mid-point Change vs. Prior Year / Mid-point $10.63 – $10.73 / $10.68 6.5% – 7.5% / 7.0% $10.50 – $10.70 / $10.60 5.2% – 7.2% / 6.2% Adjusted EPS (Diluted)3,4 / Mid-point Change vs. Prior Year / Mid-point $10.80 – $10.90 / $10.85 8.2% – 9.2% / 8.7% $10.50 – $10.70 / $10.60 5.2% – 7.2% / 6.2% 1 Non-GAAP financial measure; excludes the net impact of acquisitions and divestitures 2 Non-GAAP financial measure; excludes the impact of translational currency 3 Calculated using Euro Average Rate: July 2025 = $1.13 and April 2025 = $1.10 (Illustrative purposes only) 4 Non-GAAP financial measure; excludes intangible amortization expense and special items 5 Excludes COVID-19 Vaccine Other modeling considerations will be provided on the webcast Notable announcements in the quarter: The information contained in this section should be read together with Johnson & Johnson’s other disclosures filed with the Securities and Exchange Commission, including its Current Reports on Form 8-K, Quarterly Reports on Form 10-Q and Annual Reports on Form 10-K. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. The reader is also encouraged to review all other news releases and information available in the Investor Relations section of the company’s website at News Releases, as well as Innovative Medicine News Center, MedTech News & Events, and www.factsabouttalc.com. Regulatory Supplemental new drug application submitted to U.S. FDA for CAPLYTA® (lumateperone) with data demonstrating significant schizophrenia relapse prevention compared to placebo1 Press Release DARZALEX® (daratumumab) receives the first positive CHMP opinion for patients with high-risk smouldering multiple myeloma Press Release IMBRUVICA® (ibrutinib) receives positive CHMP opinion for the treatment of patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplant Press Release U.S. FDA Oncologic Drugs Advisory Committee votes in favor of the benefit-risk profile of DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) for high-risk smoldering multiple myeloma Press Release Johnson & Johnson receives FDA approval for IMAAVY™ (nipocalimab-aahu), a new FcRn blocker offering long-lasting disease control in the broadest population of people living with generalized myasthenia gravis (gMG) Press Release Johnson & Johnson MedTech Announces Completion of First Cases with OTTAVA™ Robotic Surgical System Press Release Data Releases IMAAVY™ (nipocalimab-aahu) showed greater sustained disease control versus approved FcRn blockers for generalized myasthenia gravis (gMG) at multiple timepoints over 24 weeks in newly published indirect treatment comparison (ITC) Press Release Investigational combination of first-in-class bispecifics TALVEY® and TECVAYLI® shows deep and durable responses in heavily pretreated multiple myeloma patients with extramedullary disease Press Release Johnson & Johnson's dual-targeting CAR T-cell therapy shows encouraging first results in large B-cell lymphoma Press Release New results for Johnson & Johnson's bleximenib demonstrate promising antileukemic activity in combination with venetoclax and azacitidine for acute myeloid leukemia Press Release Significant efficacy benefit of IMBRUVICA® (ibrutinib) plus venetoclax versus acalabrutinib plus venetoclax in frontline treatment of patients with chronic lymphocytic leukaemia suggested by indirect treatment comparison Press Release New data show TREMFYA® (guselkumab) is the only IL-23 inhibitor proven to significantly inhibit progression of joint structural damage in active psoriatic arthritis Press Release DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)-based regimen shows 95 percent progression-free survival at four years in transplant-eligible, newly diagnosed patients with multiple myeloma who achieved sustained MRD negativity Press Release Early results from Johnson & Johnson's trispecific antibody show promising response in heavily pretreated multiple myeloma patients Press Release Single infusion of CARVYKTI® (ciltacabtagene autoleucel) delivered lasting treatment-free remissions for at least five years in patients with relapsed or refractory multiple myeloma Press Release Johnson & Johnson leads with first PARP inhibitor combo to improve efficacy in patients with HRR-altered mCSPC Press Release Johnson & Johnson unveils first-in-human results for pasritamig, showing early anti-tumor activity in prostate cancer Press Release Shockwave Medical Study Confirms Benefit of IVL-First Strategy in Real-World Female Patients with Complex Calcified Lesions in Late-Breaking Data Presentation at EuroPCR 2025 Press Release Icotrokinra results show significant skin clearance in patients with difficult-to-treat scalp and genital psoriasis Press Release TREMFYA® (guselkumab) delivers sustained clinical and endoscopic remission in ulcerative colitis through two years Press Release TREMFYA® (guselkumab) positioned to become the first and only IL-23 inhibitor to offer subcutaneous induction in ulcerative colitis as demonstrated in new data through 24 weeks Press Release Johnson & Johnson's TAR-200 monotherapy achieves high disease-free survival of more than 80 percent in BCG-unresponsive, high-risk papillary NMIBC Press Release Johnson & Johnson's TAR-200 monotherapy demonstrates highest complete response rate with sustained clinical benefits in patients with certain types of bladder cancer Press Release Johnson & Johnson MedTech Presents 3-Month Data from Omny-IRE Clinical Trial at 2025 Heart Rhythm Society Annual Meeting Press Release Product Launch Johnson & Johnson Launches First and Only Daily Disposable Multifocal Toric Contact Lens - ACUVUE OASYS MAX 1-Day MULTIFOCAL for ASTIGMATISM Press Release Johnson & Johnson Launches VOLT™ Wrist and Proximal Humerus Plating Systems in the U.S. Press Release Johnson & Johnson Launches New TECNIS Odyssey Next-Generation Intraocular Lens in Europe, the Middle East, and Canada Offering Cataract Patients Precise Vision at Every Distance in Any Lighting Press Release Johnson & Johnson Launches KINCISE™ 2 System, the Only Automated Surgical Impactor Approved for Knee and Hip Revision Procedures Press Release Johnson & Johnson MedTech Launches SOUNDSTAR CRYSTAL™ in the US, Redefining Image Clarity in 2D Intracardiac Imaging Press Release Other Johnson & Johnson Elects Daniel Pinto, President, JPMorganChase to its Board of Directors Press Release 1 Subsequent to the quarter Webcast information: Johnson & Johnson will conduct a conference call with investors to discuss this earnings release today at 8:30 a.m., Eastern Time. A simultaneous webcast of the call for investors and other interested parties may be accessed by visiting the Johnson & Johnson website. A replay and podcast will be available approximately two hours after the live webcast in the Investor Relations section of the company's website at events-and-presentations. 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 www.jnj.com. Non-GAAP financial measures: * “Operational sales growth” excluding the impact of translational currency, “adjusted operational sales growth” excluding the net impact of acquisitions and divestitures and translational currency, as well as “adjusted net earnings”, “adjusted diluted earnings per share” and “adjusted operational diluted earnings per share” excluding after-tax intangible amortization expense and special items, are non-GAAP financial measures and should not be considered replacements for, and should be read together with, the most comparable GAAP financial measures. Except for guidance measures, reconciliations of these non-GAAP financial measures to the most directly comparable GAAP financial measures can be found in the accompanying financial schedules of the earnings release and the Investor Relations section of the company's website at quarterly results. Copies of the financial schedules accompanying this earnings release are available on the company’s website at quarterly results. These schedules include supplementary sales data, a condensed consolidated statement of earnings, reconciliations of non-GAAP financial measures, and sales of key products/franchises. Additional information on Johnson & Johnson, including adjusted income before tax by segment, an Innovative Medicine pipeline of selected compounds in late stage development and a copy of today’s earnings call presentation can also be found in the Investor Relations section of the company's website at quarterly results. Note to investors concerning forward-looking statements: This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things: future operating and financial performance, product development, and market position and business strategy. 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: economic factors, such as interest rate and currency exchange rate fluctuations or changes to applicable laws and regulations; competition, including technological advances, new products and patents attained by competitors; challenges inherent in new product research and development, including uncertainty of clinical success and obtaining regulatory approvals; uncertainty of commercial success for new and existing products; challenges to patents; the impact of patent expirations; the ability of the Company to successfully execute strategic plans, including restructuring plans; the impact of business combinations and divestitures; manufacturing difficulties or delays, internally or within the supply chain; product efficacy or safety concerns resulting in product recalls or regulatory action; significant adverse litigation or government action, including related to product liability claims; changes to applicable laws and regulations, including tax laws and global health care reforms; trends toward health care cost containment; changes in behavior and spending patterns of purchasers of health care products and services; financial instability of international economies and legal systems and sovereign risk; and increased scrutiny of the health care industry by government agencies. 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 www.sec.gov, www.jnj.com, investor.jnj.com, or on request from Johnson & Johnson. Any forward-looking statement made in this release speaks only as of the date of this release. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments. Percent Change Percent Change 2025 2024 Total Operations Currency 2025 2024 Total Operations Currency $ 9,161 8,510 7.6 % 7.6 - $ 17,253 16,122 7.0 % 7.0 - 6,041 5,980 1.0 (1.6 ) 2.6 11,822 11,930 (0.9 ) (0.1 ) (0.8 ) 15,202 14,490 4.9 3.8 1.1 29,075 28,052 3.6 4.0 (0.4 ) 4,383 4,059 8.0 8.0 - 8,596 8,067 6.6 6.6 - 4,158 3,898 6.7 4.1 2.6 7,965 7,711 3.3 3.6 (0.3 ) 8,541 7,957 7.3 6.1 1.2 16,561 15,778 5.0 5.1 (0.1 ) 13,544 12,569 7.8 7.8 - 25,849 24,189 6.9 6.9 - 10,199 9,878 3.2 0.6 2.6 19,787 19,641 0.7 1.4 (0.7 ) $ 23,743 22,447 5.8 % 4.6 1.2 $ 45,636 43,830 4.1 % 4.4 (0.3 ) Percent Change Percent Change 2025 2024 Total Operations Currency 2025 2024 Total Operations Currency $ 13,544 12,569 7.8 % 7.8 - $ 25,849 24,189 6.9 % 6.9 - 5,387 5,214 3.3 (1.9 ) 5.2 10,497 10,377 1.1 0.2 0.9 1,206 1,212 (0.5 ) 6.2 (6.7 ) 2,373 2,406 (1.3 ) 7.7 (9.0 ) 3,606 3,452 4.4 2.4 2.0 6,917 6,858 0.9 0.9 0.0 10,199 9,878 3.2 0.6 2.6 19,787 19,641 0.7 1.4 (0.7 ) $ 23,743 22,447 5.8 % 4.6 1.2 $ 45,636 43,830 4.1 % 4.4 (0.3 ) 2025 2024 Percent Percent Percent Increase Amount to Sales Amount to Sales (Decrease) $ 23,743 100.0 $ 22,447 100.0 5.8 7,628 32.1 6,869 30.6 11.0 16,115 67.9 15,578 69.4 3.4 5,889 24.8 5,681 25.3 3.7 3,516 14.8 3,440 15.3 2.2 - - 194 0.9 48 0.2 (125 ) (0.6 ) 107 0.5 653 2.9 64 0.3 (13 ) 0.0 6,491 27.3 5,748 25.6 12.9 954 4.0 1,062 4.7 (10.2 ) $ 5,537 23.3 $ 4,686 20.9 18.2 $ 2.29 $ 1.93 18.7 2,419.1 2,422.0 14.7 % 18.5 % $ 8,188 34.5 $ 8,404 37.4 (2.6 ) $ 6,699 28.2 $ 6,840 30.5 (2.1 ) $ 2.77 $ 2.82 (1.8 ) 18.2 % 18.6 % 2025 2024 Percent Percent Percent Increase Amount to Sales Amount to Sales (Decrease) $ 45,636 100.0 $ 43,830 100.0 4.1 14,985 32.8 13,380 30.5 12.0 30,651 67.2 30,450 69.5 0.7 11,001 24.1 10,938 25.0 0.6 6,741 14.8 6,982 16.0 (3.5 ) - - 194 0.4 (80 ) (0.2 ) (334 ) (0.8 ) (7,214 ) (15.8 ) 3,057 7.0 81 0.2 151 0.3 20,122 44.1 9,462 21.6 112.7 3,586 7.9 1,521 3.5 135.8 $ 16,536 36.2 $ 7,941 18.1 108.2 $ 6.82 $ 3.27 108.6 2,423.3 2,428.5 17.8 % 16.1 % $ 16,199 35.5 $ 16,281 37.1 (0.5 ) $ 13,405 29.4 $ 13,420 30.6 (0.1 ) $ 5.53 $ 5.53 0.0 17.2 % 17.6 % 2025 2024 2025 2024 $5,537 $4,686 $16,536 $7,941 57 352 (6,909) 3,078 1,267 1,106 2,387 2,184 - 64 - 73 79 (11) 134 160 - 68 - 119 246 452 378 600 21 431 60 411 - 194 - 194 27 - 27 - (321) (437) 994 (1,293) (214) (65) (202) (47) $6,699 $6,840 $13,405 $13,420 2,419.1 2,422.0 2,423.3 2,428.5 $2.77 $2.82 $5.53 $5.53 $2.71 $5.52 1 2 4.9% 7.3% 5.8% 7.6% 8.0% 7.8% 1.0% 6.7% 3.2% 1.1 1.2 1.2 - - - 2.6 2.6 2.6 3.8% 6.1% 4.6% 7.6% 8.0% 7.8% (1.6)% 4.1% 0.6% (2.2) (0.8) (3.5) (1.1) (0.9) (0.3) (1.4) (0.9) (2.4) (1.7) 0.0 0.0 0.0 0.2 0.1 0.0 0.2 0.0 0.0 0.2 0.1 2.4% 4.1% 3.0% 5.2% 4.7% 5.0% (1.6)% 3.4% 0.4% Innovative Medicine MedTech Total 3.6% 5.0% 4.1% 7.0% 6.6% 6.9% (0.9)% 3.3% 0.7% (0.4) (0.1) (0.3) - - - (0.8) (0.3) (0.7) 4.0% 5.1% 4.4% 7.0% 6.6% 6.9% (0.1)% 3.6% 1.4% (2.7) (1.0) (4.3) (1.5) (1.1) (0.5) (0.8) (0.5) (1.3) (0.9) 0.0 0.0 0.1 0.3 0.2 0.0 0.5 0.2 0.2 0.2 0.2 3.3% 2.7% 3.1% 5.7% 2.8% 4.7% 0.1% 2.7% 1.1% REPORTED SALES vs. PRIOR PERIOD ($MM) REPORTED SALES vs. PRIOR PERIOD ($MM) SECOND QUARTER SIX MONTHS % Change % Change 2025 2024 Reported Operational (1) Currency 2025 2024 Reported Operational (1) Currency $ 3,385 2,636 28.4 % 28.4 % - $ 6,398 5,019 27.5 % 27.5 % - 2,928 2,455 19.3 % 15.7 % 3.6 % 5,592 4,885 14.5 % 15.1 % -0.6 % 6,312 5,090 24.0 % 22.3 % 1.7 % 11,990 9,904 21.1 % 21.3 % -0.2 % 358 167 * * - 676 307 * * - 81 20 * * * 132 36 * * * 439 186 * * * 808 343 * * * 2,017 1,641 23.0 % 23.0 % - 3,846 3,105 23.9 % 23.9 % - 1,521 1,237 23.0 % 19.6 % 3.4 % 2,930 2,465 18.9 % 19.7 % -0.8 % 3,539 2,878 23.0 % 21.5 % 1.5 % 6,776 5,570 21.7 % 22.0 % -0.3 % 378 318 18.6 % 18.6 % - 670 603 11.0 % 11.0 % - 530 418 27.0 % 22.8 % 4.2 % 1,009 822 22.9 % 23.0 % -0.1 % 908 736 23.4 % 21.0 % 2.4 % 1,679 1,425 17.8 % 17.9 % -0.1 % 239 246 -2.7 % -2.7 % - 474 511 -7.3 % -7.3 % - 496 525 -5.4 % -8.4 % 3.0 % 970 1,043 -6.9 % -6.3 % -0.6 % 735 770 -4.5 % -6.6 % 2.1 % 1,444 1,554 -7.0 % -6.6 % -0.4 % 139 52 * * - 252 88 * * - 41 17 * * * 69 28 * * * 179 69 * * * 320 116 * * * 82 59 38.0 % 38.0 % - 150 109 36.7 % 36.7 % - 24 9 * * * 42 17 * * * 106 69 55.0 % 54.3 % 0.7 % 192 127 52.0 % 52.4 % -0.4 % 114 104 8.2 % 8.2 % - 219 205 6.6 % 6.6 % - 52 30 74.8 % 72.0 % 2.8 % 98 63 56.0 % 58.4 % -2.4 % 166 135 23.1 % 22.4 % 0.7 % 317 268 18.2 % 18.7 % -0.5 % 6 11 -38.9 % -38.9 % - 13 20 -31.9 % -31.9 % - 139 154 -9.8 % -13.3 % 3.5 % 257 326 -21.1 % -21.3 % 0.2 % 145 165 -11.6 % -14.9 % 3.3 % 270 346 -21.7 % -21.9 % 0.2 % 50 37 36.9 % 36.9 % - 97 70 39.8 % 39.8 % - 42 45 -8.7 % -12.3 % 3.6 % 84 86 -2.5 % -1.8 % -0.7 % 93 83 11.7 % 9.7 % 2.0 % 182 156 16.4 % 16.8 % -0.4 % REPORTED SALES vs. PRIOR PERIOD ($MM) REPORTED SALES vs. PRIOR PERIOD ($MM) SECOND QUARTER SIX MONTHS % Change % Change 2025 2024 Reported Operational (1) Currency 2025 2024 Reported Operational (1) Currency $ 2,505 2,978 -15.9 % -15.9 % - $ 4,701 5,431 -13.4 % -13.4 % - 1,489 1,744 -14.6 % -16.2 % 1.6 % 2,999 3,538 -15.2 % -13.8 % -1.4 % 3,993 4,722 -15.4 % -16.0 % 0.6 % 7,700 8,969 -14.1 % -13.6 % -0.5 % 283 231 22.5 % 22.5 % - 597 497 20.1 % 20.1 % - 34 35 -2.6 % -2.6 % - 44 62 -28.7 % -28.7 % - 138 127 8.6 % 8.8 % -0.2 % 281 268 4.8 % 7.7 % -2.9 % 455 393 15.9 % 15.9 % 0.0 % 922 827 11.5 % 12.4 % -0.9 % 305 267 14.0 % 14.0 % - 597 521 14.4 % 14.4 % - 387 270 43.1 % 40.8 % 2.3 % 753 569 32.2 % 35.0 % -2.8 % 690 537 28.6 % 27.5 % 1.1 % 1,349 1,091 23.7 % 25.1 % -1.4 % 1,078 1,855 -41.9 % -41.9 % - 2,059 3,251 -36.7 % -36.7 % - 575 1,030 -44.2 % -45.6 % 1.4 % 1,219 2,085 -41.5 % -40.6 % -0.9 % 1,653 2,885 -42.7 % -43.2 % 0.5 % 3,278 5,336 -38.6 % -38.2 % -0.4 % 796 589 35.2 % 35.2 % - 1,395 1,098 27.1 % 27.1 % - 391 317 23.2 % 20.5 % 2.7 % 747 616 21.2 % 22.4 % -1.2 % 1,186 906 31.0 % 30.1 % 0.9 % 2,142 1,714 25.0 % 25.4 % -0.4 % 8 2 * * - 9 2 * * - 0 0 - - - 0 0 - - - 8 2 * * - 9 2 * * - 1,377 1,102 24.9 % 24.9 % - 2,345 2,156 8.7 % 8.7 % - 674 679 -0.8 % -2.6 % 1.8 % 1,353 1,428 -5.2 % -4.1 % -1.1 % 2,051 1,782 15.1 % 14.4 % 0.7 % 3,698 3,585 3.2 % 3.6 % -0.4 % 211 - * * - 211 - * * - - - - - - - - - - - 211 - * * - 211 - * * - 24 34 -27.7 % -27.7 % - 62 75 -16.6 % -16.6 % - 139 129 7.5 % 7.0 % 0.5 % 249 265 -6.0 % -4.4 % -1.6 % 164 163 0.2 % -0.2 % 0.4 % 312 340 -8.3 % -7.1 % -1.2 % 732 784 -6.7 % -6.7 % - 1,357 1,549 -12.4 % -12.4 % - 260 269 -3.5 % -5.1 % 1.6 % 537 561 -4.2 % -3.1 % -1.1 % 992 1,054 -5.9 % -6.3 % 0.4 % 1,895 2,110 -10.2 % -9.9 % -0.3 % 366 226 61.1 % 61.1 % - 642 417 53.7 % 53.7 % - 50 44 12.8 % 11.0 % 1.8 % 93 78 18.1 % 20.1 % -2.0 % 414 271 53.3 % 53.0 % 0.3 % 734 496 48.1 % 48.4 % -0.3 % 45 57 -23.5 % -23.5 % - 73 115 -37.0 % -37.0 % - 226 237 -4.7 % -7.6 % 2.9 % 474 524 -9.5 % -8.8 % -0.7 % 270 294 -8.4 % -10.7 % 2.3 % 547 639 -14.4 % -13.9 % -0.5 % REPORTED SALES vs. PRIOR PERIOD ($MM) REPORTED SALES vs. PRIOR PERIOD ($MM) SECOND QUARTER SIX MONTHS % Change % Change 2025 2024 Reported Operational (1) Currency 2025 2024 Reported Operational (1) Currency $ 799 743 7.6 % 7.6 % - $ 1,543 1,509 2.3 % 2.3 % - 314 296 5.8 % 2.8 % 3.0 % 595 579 2.6 % 3.0 % -0.4 % 1,113 1,039 7.1 % 6.2 % 0.9 % 2,138 2,088 2.4 % 2.5 % -0.1 % 403 376 6.9 % 6.9 % - 766 732 4.6 % 4.6 % - 180 171 5.4 % 2.1 % 3.3 % 339 340 -0.3 % -0.2 % -0.1 % 582 548 6.4 % 5.4 % 1.0 % 1,104 1,072 3.0 % 3.1 % -0.1 % 382 349 9.4 % 9.4 % - 747 741 0.8 % 0.8 % - 94 76 22.4 % 19.8 % 2.6 % 180 152 17.9 % 18.7 % -0.8 % 476 426 11.7 % 11.3 % 0.4 % 927 894 3.7 % 3.8 % -0.1 % 16 17 -12.4 % -12.4 % - 31 35 -12.6 % -12.6 % - 40 49 -18.5 % -21.3 % 2.8 % 77 88 -12.4 % -12.1 % -0.3 % 55 67 -16.9 % -19.0 % 2.1 % 107 123 -12.5 % -12.3 % -0.2 % 320 334 -4.3 % -4.3 % - 635 658 -3.6 % -3.6 % - 484 631 -23.4 % -26.8 % 3.4 % 971 1,128 -13.9 % -14.1 % 0.2 % 803 965 -16.8 % -19.0 % 2.2 % 1,605 1,786 -10.1 % -10.2 % 0.1 % 6 8 -25.4 % -25.4 % - 14 16 -13.6 % -13.6 % - 354 288 23.0 % 16.7 % 6.3 % 704 603 16.7 % 15.6 % 1.1 % 360 297 21.6 % 15.5 % 6.1 % 718 620 15.9 % 14.9 % 1.0 % 312 321 -3.0 % -3.0 % - 617 635 -2.9 % -2.9 % - 85 117 -27.0 % -29.4 % 2.4 % 183 221 -17.2 % -15.8 % -1.4 % 396 438 -9.4 % -10.0 % 0.6 % 799 856 -6.6 % -6.3 % -0.3 % 2 5 -51.8 % -51.8 % - 4 7 -37.4 % -37.4 % - 45 227 -80.5 % -80.6 % 0.1 % 84 304 -72.5 % -72.1 % -0.4 % 47 233 -79.8 % -79.9 % 0.1 % 88 311 -71.7 % -71.3 % -0.4 % 776 717 8.2 % 8.2 % - 1,631 1,348 21.0 % 21.0 % - 154 176 -12.3 % -13.2 % 0.9 % 312 373 -16.2 % -14.3 % -1.9 % 930 892 4.2 % 4.0 % 0.2 % 1,943 1,721 12.9 % 13.3 % -0.4 % 621 587 5.6 % 5.6 % - 1,311 1,105 18.6 % 18.6 % - - - - - - - - - - - 621 587 5.6 % 5.6 % - 1,311 1,105 18.6 % 18.6 % - 155 129 20.0 % 20.0 % - 320 243 31.6 % 31.6 % - 154 176 -12.3 % -13.2 % 0.9 % 312 373 -16.2 % -14.3 % -1.9 % 309 305 1.4 % 0.9 % 0.5 % 632 616 2.7 % 3.9 % -1.2 % 9,161 8,510 7.6 % 7.6 % - 17,253 16,122 7.0 % 7.0 % - 6,041 5,980 1.0 % -1.6 % 2.6 % 11,822 11,930 -0.9 % -0.1 % -0.8 % $ 15,202 14,490 4.9 % 3.8 % 1.1 % $ 29,075 28,052 3.6 % 4.0 % -0.4 % REPORTED SALES vs. PRIOR PERIOD ($MM) REPORTED SALES vs. PRIOR PERIOD ($MM) SECOND QUARTER SIX MONTHS % Change % Change 2025 2024 Reported Operational (1) Currency 2025 2024 Reported Operational (1) Currency $ 1,364 1,119 21.9 % 21.9 % - $ 2,625 2,144 22.4 % 22.4 % - 948 753 25.9 % 22.9 % 3.0 % 1,790 1,534 16.7 % 16.7 % 0.0 % 2,313 1,873 23.5 % 22.3 % 1.2 % 4,416 3,679 20.0 % 20.0 % 0.0 % 741 705 5.1 % 5.1 % - 1,425 1,397 2.0 % 2.0 % - 728 618 17.8 % 15.2 % 2.6 % 1,366 1,270 7.6 % 7.8 % -0.2 % 1,468 1,323 11.0 % 9.8 % 1.2 % 2,791 2,667 4.7 % 4.7 % 0.0 % 360 309 16.6 % 16.6 % - 699 612 14.2 % 14.2 % - 89 72 25.0 % 18.4 % 6.6 % 170 139 22.4 % 20.9 % 1.5 % 448 379 18.2 % 16.9 % 1.3 % 868 750 15.7 % 15.5 % 0.2 % 233 77 * * - 439 77 * * - 58 0 * * * 110 0 * * * 292 77 * * * 550 77 * * - 31 29 5.4 % 5.4 % - 63 59 6.3 % 6.3 % - 72 64 13.4 % 11.6 % 1.8 % 144 126 14.2 % 14.5 % -0.3 % 104 93 10.8 % 9.7 % 1.1 % 207 185 11.7 % 11.8 % -0.1 % 1,420 1,422 -0.2 % -0.2 % - 2,804 2,870 -2.3 % -2.3 % - 885 890 -0.5 % -4.0 % 3.5 % 1,742 1,782 -2.2 % -2.4 % 0.2 % 2,305 2,312 -0.3 % -1.6 % 1.3 % 4,546 4,652 -2.3 % -2.3 % 0.0 % 271 265 2.1 % 2.1 % - 534 535 -0.2 % -0.2 % - 150 152 -1.0 % -4.3 % 3.3 % 296 304 -2.5 % -2.6 % 0.1 % 421 417 1.0 % -0.2 % 1.2 % 830 839 -1.1 % -1.1 % 0.0 % 226 230 -1.9 % -1.9 % - 457 472 -3.1 % -3.1 % - 164 163 0.0 % -2.9 % 2.9 % 322 323 -0.5 % -0.4 % -0.1 % 389 394 -1.1 % -2.3 % 1.2 % 778 795 -2.0 % -2.0 % 0.0 % 501 498 0.7 % 0.7 % - 1,003 1,002 0.1 % 0.1 % - 267 260 2.2 % -1.5 % 3.7 % 537 521 2.9 % 2.8 % 0.1 % 768 759 1.2 % -0.1 % 1.3 % 1,540 1,524 1.1 % 1.0 % 0.1 % 422 430 -1.7 % -1.7 % - 810 862 -6.0 % -6.0 % - 305 314 -2.7 % -6.4 % 3.7 % 588 634 -7.2 % -7.7 % 0.5 % 727 743 -2.1 % -3.7 % 1.6 % 1,398 1,495 -6.5 % -6.7 % 0.2 % REPORTED SALES vs. PRIOR PERIOD ($MM) REPORTED SALES vs. PRIOR PERIOD ($MM) SECOND QUARTER SIX MONTHS % Change % Change 2025 2024 Reported Operational (1) Currency 2025 2024 Reported Operational (1) Currency $ 1,043 995 4.8 % 4.8 % - $ 2,045 1,982 3.2 % 3.2 % - 1,512 1,493 1.3 % -0.2 % 1.5 % 2,906 2,922 -0.5 % 0.3 % -0.8 % 2,555 2,488 2.7 % 1.8 % 0.9 % 4,951 4,904 1.0 % 1.5 % -0.5 % 477 466 2.2 % 2.2 % - 934 912 2.4 % 2.4 % - 687 675 1.9 % 0.2 % 1.7 % 1,303 1,316 -1.0 % -0.4 % -0.6 % 1,164 1,141 2.0 % 1.0 % 1.0 % 2,237 2,228 0.4 % 0.8 % -0.4 % 567 528 7.2 % 7.2 % - 1,111 1,070 3.8 % 3.8 % - 825 818 0.9 % -0.6 % 1.5 % 1,603 1,606 -0.1 % 0.8 % -0.9 % 1,391 1,346 3.3 % 2.5 % 0.8 % 2,714 2,676 1.4 % 2.0 % -0.6 % 557 523 6.5 % 6.5 % - 1,123 1,070 4.9 % 4.9 % - 813 763 6.5 % 3.4 % 3.1 % 1,526 1,473 3.6 % 3.7 % -0.1 % 1,369 1,285 6.5 % 4.6 % 1.9 % 2,648 2,543 4.1 % 4.2 % -0.1 % 429 409 4.8 % 4.8 % - 881 847 3.9 % 3.9 % - 536 509 5.4 % 1.4 % 4.0 % 1,003 981 2.3 % 1.9 % 0.4 % 965 918 5.1 % 2.9 % 2.2 % 1,884 1,828 3.1 % 2.8 % 0.3 % 128 113 12.6 % 12.6 % - 242 223 8.5 % 8.5 % - 277 254 8.8 % 7.3 % 1.5 % 523 492 6.2 % 7.2 % -1.0 % 403 367 9.9 % 8.9 % 1.0 % 764 715 6.9 % 7.6 % -0.7 % 4,383 4,059 8.0 % 8.0 % - 8,596 8,067 6.6 % 6.6 % - 4,158 3,898 6.7 % 4.1 % 2.6 % 7,965 7,711 3.3 % 3.6 % -0.3 % $ 8,541 7,957 7.3 % 6.1 % 1.2 % $ 16,561 15,778 5.0 % 5.1 % -0.1 % Second Quarter June 29, 2025 GAAP Intangible asset amortization Litigation related Restructuring related Acquisition, integration and divestiture related (Loss)/gain on securities Tax legislation and other tax related Other Second Quarter June 29, 2025 Non-GAAP $ 3,978 (785 ) (13 ) 3,180 2,789 2,789 2,869 2,869 14 69 (207 ) 8 (13 ) (129 ) 5,552 785 (69 ) - 220 (8 ) - 13 6,493 $ 3,638 (482 ) (15 ) 1 3,142 2,862 2,862 647 43 690 190 (83 ) (64 ) (53 ) (29 ) (14 ) (53 ) 1,204 482 83 79 9 29 - 14 1,900 $ 12 12 238 238 - - 15 (43 ) (17 ) (45 ) (265 ) - 43 - 17 - - - (205 ) $ 7,628 (1,267 ) (15 ) (12 ) 6,334 5,889 5,889 3,516 43 3,559 107 (57 ) (277 ) (21 ) (27 ) (275 ) - - 48 48 64 (64 ) - 6,491 1,267 57 79 246 21 - 27 8,188 954 222 9 13 72 5 214 - 1,489 5,537 1,045 48 66 174 16 (214 ) 27 6,699 $ 3,603 (694 ) (4 ) 2,905 2,665 2,665 2,722 (10 ) 2,712 41 (43 ) (194 ) 63 (1 ) (70 ) (50 ) (254 ) 5,459 694 43 194 (63 ) 1 70 - 64 - 6,462 $ 3,248 (412 ) (2 ) (50 ) (30 ) 2,754 2,671 (5 ) 2,666 718 (15 ) (33 ) 670 231 4 (50 ) (344 ) (22 ) (181 ) 1,089 412 (4 ) - 52 409 22 68 - - 2,048 $ 18 18 345 345 - - 437 (313 ) (42 ) (339 ) (257 ) (800 ) - 313 - - 42 339 - - - (106 ) $ 6,869 (1,106 ) (2 ) (50 ) (30 ) (4 ) 5,677 5,681 (5 ) 5,676 3,440 (15 ) (33 ) (10 ) 3,382 653 (352 ) (387 ) (431 ) (50 ) (567 ) 194 (194 ) - (125 ) (125 ) (13 ) 13 - 5,748 1,106 352 194 (11 ) 452 431 68 64 - 8,404 1,062 156 70 43 (6 ) 125 21 14 14 65 1,564 4,686 950 282 151 (5 ) 327 410 54 50 (65 ) 6,840 Johnson & Johnson and Subsidiaries GAAP to Non-GAAP Reconciliation $ in Millions $ 7,998 (1,434 ) (13 ) 6,551 5,050 5,050 5,417 5,417 (152 ) 69 (227 ) (10 ) (13 ) (333 ) 10,762 1,434 (69 ) - 240 10 - 13 12,390 $ 6,964 (953 ) (23 ) (51 ) 5,937 5,518 5,518 1,324 37 1,361 130 (83 ) (111 ) (107 ) (50 ) (14 ) (235 ) 2,625 953 83 134 121 50 - 14 3,980 $ 23 23 433 433 - - (7,191 ) 6,923 (17 ) (285 ) 6,735 - (6,923 ) - 17 - - - (171 ) $ 14,985 (2,387 ) (23 ) (64 ) 12,511 11,001 11,001 6,741 37 6,778 (7,214 ) 6,909 (30 ) (351 ) (60 ) (27 ) (773 ) - - (80 ) (80 ) 81 (81 ) - 20,122 2,387 (6,909 ) 134 378 60 - 27 16,199 3,586 410 (1,544 ) 24 102 14 202 2,794 16,536 1,977 (5,365 ) 110 276 46 (202 ) 27 13,405 $ 6,973 (1,392 ) (6 ) 5,575 5,103 5,103 5,618 (17 ) 5,601 (70 ) (43 ) (194 ) (81 ) (48 ) (15 ) (50 ) (501 ) 10,428 1,392 43 194 81 48 15 - 73 - 12,274 $ 6,368 (792 ) (9 ) (50 ) (50 ) 5,467 5,253 (9 ) 5,244 1,364 (33 ) (60 ) 1,271 184 4 (70 ) (387 ) (44 ) (313 ) 2,609 792 (4 ) - 79 470 44 119 - - 4,109 $ 39 39 582 582 - - 2,954 (3,039 ) (82 ) (352 ) (519 ) (3,575 ) - 3,039 - - 82 352 - - - (102 ) $ 13,380 (2,184 ) (9 ) (50 ) (50 ) (6 ) 11,081 10,938 (9 ) 10,929 6,982 (33 ) (60 ) (17 ) 6,872 3,057 (3,078 ) (517 ) (411 ) (50 ) (999 ) 194 (194 ) - (334 ) (334 ) 151 (151 ) - 9,462 2,184 3,078 194 160 600 411 119 73 - 16,281 1,521 304 697 43 33 163 14 23 16 47 2,861 7,941 1,880 2,381 151 127 437 397 96 57 (47 ) 13,420 Media contact: media-relations@its.jnj.com Investor contact: investor-relations@its.jnj.com

IL-23的生物学特性与信号通路1IL-23的分子结构◆IL-23与IL-12：IL-23是由p19亚基(特异性亚基)和p40亚基(与IL-12共享)组成的异源二聚体细胞因子，分子量约59kDa，属于IL-12细胞因子家族。虽与IL-12共享p40亚基，但IL-23主要驱动Th17细胞分化，而IL-12偏向促进Th1细胞发育。二者通过共享p40亚基实现部分信号交叉，但下游效应细胞和疾病关联差异显著。图1 IL-23和IL-12的对比◆ IL-23的受体复合物：IL-23的受体复合物是由IL-23R和IL-12Rβ1组成，IL-23的p19亚基与IL-23R结合，p40亚基与IL-12Rβ1结合，形成具有信号传导能力的复合物。图2 由IL-23与其受体复合物的相互作用触发的信号级联反应2IL-23的表达调控与靶细胞◆ IL-23的细胞来源：IL-23主要由单核细胞、巨噬细胞、树突状细胞(DCs)等组织驻留髓样细胞在炎症或感染刺激下分泌产生。此外，皮肤角质形成细胞在炎症状态下也可表达IL-23，但正常皮肤中表达水平极低。◆ IL-23的环境调控因素：缺氧(HIF-1α)、脂质代谢异常及肠道微生物信号可增强IL-23表达，促进炎症微环境形成。◆ IL-23的靶细胞类型：IL-23主要作用于表达IL-23受体和转录因子RORγt的"17型细胞"。①适应性免疫细胞：Th17细胞、Tc17细胞(CD8+IL-17+细胞)，诱导角质形成细胞的增殖(如银屑病)、中性粒细胞的募集和组织损伤。②固有免疫细胞：γδT细胞、自然杀伤T细胞(NKT)、黏膜相关恒定T细胞(MAIT)、3型固有淋巴细胞(ILC3)，协同放大炎症反应，尤其在肠道和皮肤屏障中起关键作用。③特殊群体：少数IFN-γ+Th1细胞也表达IL-23受体，在IBD中可诱导结肠炎相关基因表达。图3 IL-23的细胞来源以及靶细胞3IL-23的信号传导机制◆IL-23的信号传导：IL-23与受体复合物结合后激活JAK-STAT通路，募集JAK2和TYK2激酶，磷酸化信号转导子和转录激活子(STAT3、STAT4)，驱动Th17细胞分化和效应因子表达。◆IL-23的正反馈调控：STAT3的激活可上调RORγt、IL-23R等基因，形成正反馈环路，放大炎症信号。◆ IL-23的下游效应分子①促炎细胞因子：诱导Th17和"17型细胞"产生IL-17A、IL-17F、IL-22、GM-CSF、TNF-α等促炎细胞因子，介导细胞增殖、血管生成和免疫细胞浸润。②免疫细胞调控：抑制调节性T细胞(Tregs)分化，促进组织驻留记忆T细胞(TRM)扩增，维持慢性炎症状态。图4 IL-23的相关信号通路IL-23的生理功能与病理作用1IL-23的生理功能参与宿主防御(如抗胞外细菌和真菌感染)、维持肠道屏障稳态(通过IL-22促进上皮修复)，但过度激活可引发免疫病理。图5 与IL-23/IL-23R轴相关的时间表2IL-23R遗传变异与疾病IL-23R是I型细胞因子受体，位于人染色体1p31.3，mRNA长2.8kb，编码629个氨基酸，分子量约71.7kDa，由胞外区、跨膜区和胞内区组成，可通过选择性剪接产生多种异构体。图6 IL-23R的结构◆保护性变异①R381Q(rs11209026)：胞内域变异，减少IL-23诱导的STAT3磷酸化，降低IL-17和IL-22分泌，在欧洲人群中频率约5%，降低CD、UC、和银屑病的风险，但增加类风湿关节炎风险。②G149R(rs76418789)：胞外域变异，导致IL-23R在内质网中滞留，减少细胞表面表达，在亚洲人群中更常见(3.7%)，与UC风险降低相关。③V362I(rs41313262)：跨膜域变异，降低IL-23R稳定性，减少信号传导，保护作用尚不明确。◆风险变异①rs10889677：3'UTR变异，增强IL-23R mRNA的稳定性，与CD、UC、乳腺癌、肝癌和膀胱癌风险增加相关。②Q3H(rs1884444)：信号肽变异，增加胃癌、食管癌风险，但可能降低UC和银屑病风险。表1 在不同人群和疾病中IL-23R的遗传变异3IL-23/IL-23R轴的病理作用◆ 免疫介导炎症性疾病(IMIDs)①皮肤：在银屑病(PsO)中，IL-23刺激角质形成细胞分泌IL-20家族因子，协同TNF-α导致表皮增厚和血管生成，同时促进TRM扩增，引发慢性复发。②肠道：在炎症性肠炎(IBD)中，IL-23通过Th17细胞和ILC3s破坏肠黏膜屏障，促进细菌易位和持续性炎症，同时抑制Tregs细胞功能，加剧结肠炎症。③关节：在银屑病关节炎(PsA)中，IL-23驱动肌腱附着点(enthesis)的CD3+RORγt+细胞分泌IL-17和IL-22，诱导骨侵蚀和新骨形成，与脊柱关节炎的病理相关。图7 IL-23/IL-23R轴在发炎的肠粘膜中协调先天性和适应性免疫反应表2 IL-23/IL-23R轴在粘膜稳态和疾病中的作用◆疼痛与炎症的交互作用①外周敏化：IL-23通过诱导巨噬细胞分泌IL-17，激活背根神经节(DRG)中的TRPV1和TRPA1离子通道，增强痛觉神经元兴奋性。②中枢机制：在神经炎症中，IL-23激活小胶质细胞和星形胶质细胞，释放前列腺素(COX通路)和白三烯(LOX通路)，加剧中枢敏化和慢性疼痛。图8 IL-23/IL-23R轴在疼痛相关炎症机制中的作用◆ 肿瘤①促进肿瘤生长：在部分癌症如结直肠癌、胃癌中，IL-23/IL-23R通路引发的慢性炎症为肿瘤生长营造有利环境，利于癌细胞存活、增殖和转移。同时，该轴能抑制抗肿瘤免疫反应，阻碍细胞毒性T细胞发挥作用，使肿瘤逃避免疫监视。②抑制肿瘤生长：在特定情况下，IL-23R激活能增强机体对肿瘤的免疫反应，通过促进免疫细胞的招募和活化来对抗肿瘤。③与肿瘤遗传易感性相关：IL-23R基因存在多种单核苷酸多态性(SNPs)，这些变异与多种癌症的发生风险紧密相连。④影响肿瘤预后：在多种癌症中，IL-23R的表达水平及基因多态性与肿瘤大小、分期、转移情况以及患者预后相关。例如，乳腺癌组织中IL-23R基因表达水平与肿瘤大小、TNM分期和转移正相关；胃癌中，IL-23R阳性的肿瘤组织与更大肿瘤尺寸、更差T分期和更差临床预后相关。图9 肿瘤中IL-23R的变异及IL-23R在单细胞和T细胞谱系中的表达IL-23/IL-23R轴相关的靶向疗法1靶向IL-23p19亚基的单克隆抗体◆作用机制：特异性结合IL-23的p19亚基，阻断其与IL-23R结合，抑制下游炎症信号(如IL-17、IL-22)。◆ 代表药物：①瑞莎珠单抗(Risankizumab)：获批用于CD，显著改善临床缓解率和内镜应答。②米罗珠单抗(Mirikizumab)：获批用于UC，对黏膜愈合效果显著。③古塞库单抗(Guselkumab)：在CD和UC中均显示疗效。图10 IL-23p19单克隆抗体的分子结构和差异2靶向IL-23p40亚基的单克隆抗体◆作用机制：靶向IL-12/IL-23共享的p40亚基，用于PsO、IBD等疾病治疗中，能显著改善症状。但由于同时作用于IL-12和IL-23，可能会影响IL-12的免疫监视功能，带来一定副作用。◆代表药物：①优特克单抗(Ustekinumab)：获批用于中重度CD和UC，但可能影响IL-12通路。表3 正在进行临床试验的抗IL-23单克隆抗体3靶向IL-23/IL-23R轴的药物◆口服IL-23R拮抗剂(如PTG-200)：设计能够与IL-23R结合的小分子肽类药物，竞争性抑制IL-23与IL-23R的相互作用，通过阻断IL-23R信号，改善肠道渗透性，在IBD动物模型中显示潜力。 与传统抗体药物相比，它具有更好的组织特异性、分子量小、生产成本低等优点，能避免全身免疫抑制。◆TYK2抑制剂(如Deucravacitinib)：抑制下游信号通路，在PsO中有效，IBD临床试验正在进行。◆JAK抑制剂(如Tofacitinib、Upadacitinib)：可抑制JAK家族激酶(如Tyk2、Jak2)的活性，从而阻断IL-23/IL-23R信号通路下游的STAT磷酸化和基因表达。表4 用于IBD治疗的JAK抑制剂◆STAT3抑制剂：开发针对STAT3的小分子抑制剂，可阻止其磷酸化和核转位，进而抑制IL-23诱导的Th17细胞分化和炎症因子分泌。◆ RORγt抑制剂：RORγt是Th17细胞分化的关键转录因子，抑制RORγt可减少Th17细胞的生成和功能，从而减轻炎症反应。4其他治疗策略◆融合蛋白：通过将IL-23R的胞外域与免疫球蛋白的Fc段融合，构建可溶性的IL-23R-Fc融合蛋白，可竞争性结合IL-23，阻断其与细胞表面IL-23R的相互作用。◆基因编辑：通过CRISPR-Cas9等基因编辑技术，靶向修饰IL-23R基因，减少其表达或功能，从而抑制IL-23/IL-23R信号通路。◆Alphabody：是一种蛋白质支架，可特异性结合IL-23的p19亚基，阻止其与IL-23R结合，从而抑制IL-23的信号传导。◆ 联合治疗：将靶向IL-23/IL-23R的治疗策略与其他免疫治疗(如PD-1/PD-L1抑制剂)、化疗、放疗、表观遗传调控(如HIF-1α抑制剂)或代谢干预(如脂质代谢调控)等联合使用，以增强抗肿瘤效果或改善自身免疫性疾病的治疗效果。IL-23/IL-23R轴与炎症性疾病1银屑病(PsO)◆致病机制：IL-23由皮损皮肤中的FcγRI/CD64+单核细胞/巨噬细胞、单核吞噬细胞及半成熟树突状细胞产生，激活Th17/17型细胞，诱导其释放释放IL-17A/F和IL-22，促进角质形成细胞增殖、血管生成及免疫细胞浸润，形成炎症级联反应，引发红斑、鳞屑和关节炎症。此外，IL-23还促进TRM细胞扩增，导致皮损复发和疾病慢性化。◆遗传学研究：IL-23R基因变异与银屑病易感性相关，HLA-C*06:02等位基因可增强对IL-23抑制剂的临床反应。◆临床治疗：临床数据显示，靶向IL-23p19亚基的抑制剂(如Guselkumab)已批准用于治疗中度至重度斑块PsO，逆转皮损转录组异常，显著改善皮肤症状，疗效优于IL-17A抑制剂(如Secukinumab)，停药后仍能通过持续抑制IL-23/IL-23R轴维持长期缓解。图11 IBD和PsO的常见发病机制2银屑病关节炎(PsA)◆ 致病机制：人类肌腱端组织中的ILC3s可表达IL-23，参与SpA样病变的病理过程。IL-23在PsA中诱导肌腱端炎和新骨形成，通过激活局部CD3+淋巴细胞分泌IL-17和IL-22，促进滑膜血管翳形成和骨破坏。◆遗传学研究：脊柱关节病和相关疾病(如PsA)的易感性与IL-23通路相关基因多态性有关，包括编码IL-23A和IL-23R、JAK2和TYK2、STAT3和IL-17RA的基因多态性。◆临床治疗：IL-23p19抑制剂(如Risankizumab)可调节全血中PsA相关基因表达，改善关节和皮肤症状，且安全性优于TNF或IL-17抑制剂。3炎症性肠病(IBD)◆ 致病机制：肠道中IL-23由单核细胞、巨噬细胞和中性粒细胞分泌，促进Th17细胞扩增并抑制Treg细胞，破坏肠黏膜屏障，加剧炎症。克罗恩病(CD)中，IL-23还可诱导Th1细胞表达结肠炎相关基因(如IFN-γ)，加剧透壁性炎症；溃疡性结肠炎(UC)中，IL-23与IL-17A/F协同促进黏膜溃疡。◆遗传学研究：IL-23R基因变异与IBD易感性强相关，全基因组关联研究(GWAS)显示IL-23信号通路基因与IBD病理机制相关。◆临床影响：瑞莎珠单抗和米罗珠单抗已获批用于CD和UC，显著改善临床缓解率和内镜愈合，且对结肠和回肠的基因表达有差异化调节作用，提示IL-23在不同肠段的作用异质性。图12 肠粘膜中的IL23信号传导4其他炎症性疾病◆轴向脊柱关节炎(AxialSpA)：动物模型显示IL-23参与发病，但临床试验中IL-23抑制剂对轴向病变无效，可能与病变部位(如骶髂关节)药物渗透不足或依赖其他细胞因子(如IL-12)有关。猜测IL-23可能仅在AxialSpA早期驱动炎症，而晚期病变以其他通路为主。◆类风湿关节炎(RA)：在佐剂性关节炎模型中，IL-23缺失可完全抑制炎症和疼痛，表明其通过激活Th17细胞和中性粒细胞，促进关节破坏和痛觉敏化。但临床试验中IL-23抑制剂未能改善RA症状，可能与人类RA中IL-23作用较弱相关。◆多发性硬化(MS)：在实验性自身免疫性脑脊髓炎(EAE)模型中，IL-23促进Th17细胞存活和中枢神经系统炎症，加剧脱髓鞘病变。但IL-12/IL-23p40抑制剂均对MS无效，因IL-23仅在MS发病早期起作用，且药物难以透过血脑屏障。5潜在关联疾病对IL-23抑制剂治疗表现出有希望反应的疾病包括化脓性汗腺炎、扁平苔藓、毛发红糠疹、坏疽性脓皮病、头皮夹层蜂窝织炎、先天性鱼鳞病样红皮病、类天疱疮扁平苔藓、肢端面部白斑病、毛发扁平苔藓、额叶纤维化脱发、红斑狼疮和Stewart-Treves血管肉瘤等，但针对这些情况的临床试验不足，这限制了对其安全性和有效性得出明确结论的能力。表5 IL-23抑制剂的标签外皮肤病学用途IL-23/IL-23R轴与肿瘤1食管癌在食管鳞癌细胞中，IL-23与IL-23R结合，激活STAT3/Wnt/Notch信号通路。一方面，调节p21、p-rb以及CDK4/6等周期调控关键蛋白表达，使癌细胞进入G0/1期阻滞，产生放疗抵抗；另一方面，诱导上皮-间质转化(EMT)，促使癌细胞迁移和侵袭。IL-23R基因多态性影响食管癌发病风险，如rs6682925T>C和rs1884444T>G变异会增加患病风险，而rs10889677A>C可能有保护作用。检测IL-23R基因多态性，可评估个体患食管癌的风险，指导个性化预防和治疗。2胃癌IL-23R参与Th17细胞介导的炎症过程，在胃癌发病中起重要作用。IL-23与IL-23R结合后，通过STAT3信号通路诱导EMT，促进胃癌细胞的迁移和侵袭。IL-23R基因多态性与胃癌预后相关，如rs1884444的G等位基因与降低胃癌风险有关，且在肠型胃癌中更明显。检测IL-23R基因多态性有助于评估胃癌患者的预后情况，为制定个性化治疗方案提供依据。3结直肠癌在IBD中，持续的炎症刺激可能促使结直肠癌发生。 IL-23可能通过与髓系细胞表达的IL-23R结合，抑制Th1细胞和促进MDSC细胞的产生，进而促进结直肠炎相关结直肠癌的进展。 此外，IL-23R+Th17细胞参与调节IL-23驱动的结肠炎相关肿瘤形成和散发性结肠肿瘤的进展。4乳腺癌IL-23R基因表达水平与乳腺癌肿瘤大小、TNM分期和转移相关。 IL-23/IL-23R通路可能通过调节免疫微环境，影响肿瘤细胞的增殖、侵袭和转移能力。 IL-23R基因多态性如rs1884444与HER-2状态及肿瘤大小有关，可能参与乳腺癌的早期发展。 IL-23R基因表达水平和多态性检测可作为乳腺癌潜在的预后标志物和治疗靶点，有助于评估患者预后和制定个性化治疗方案。5膀胱癌IL-23R是Th17细胞启动的关键正调节因子，可激活IL-23/17炎症轴，参与膀胱癌的发生发展。 IL-23R的某些变异(如rs10889677C)与膀胱癌发病风险相关，而rs1884444G/T变异与降低膀胱癌风险相关。 检测IL-23R基因变异可用于膀胱癌的风险评估和预后判断。6肝细胞癌IL-23R基因变异与肝细胞癌发病风险有关，如野生型IL-23RGG基因型是风险因素，rs11209026有保护作用。 多个多态性位点如rs10889677、rs1884444等与肝细胞癌风险相关。 IL-23/IL-23R通路可能通过影响免疫细胞功能和肿瘤微环境，促进肿瘤细胞的增殖、存活和转移。 通过检测IL-23R基因多态性，可对肝细胞癌高危人群进行筛查和风险评估。7多发性骨髓瘤IL-23R在正常血浆细胞和多发性骨髓瘤细胞上均有表达。 骨髓瘤患者血清中IL-23明显增高，与Tregs细胞水平呈负相关，打破Treg/Th17的平衡，IL-23与Treg共同推动瘤细胞的恶性增殖。 IL-23R的HH基因型(rs1884444TT)与骨病变和浆细胞瘤的发生相关，影响患者生存率。 检测IL-23R基因多态性有助于评估多发性骨髓瘤患者的病情严重程度和预后，针对携带特定基因型的患者选择更有效的治疗药物。现有优势与未来方向1现有优势◆ 疗效持久：相比IL-17A抑制剂，IL-23抑制剂通过抑制上游调控因子，更全面地阻断17型免疫网络，并减少TRM细胞介导的复发。◆ 安全性好：①感染风险：与安慰剂相比，严重感染和机会性感染发生率低，无显著增加真菌感染或结核风险。②肿瘤与心血管事件：长期随访显示恶性肿瘤和主要心血管事件(MACE)发生率与对照组无差异。③免疫原性：抗药物抗体(ADA)发生率低，不影响疗效。表6 IL-23阻断剂的不良事件发生率2研究挑战◆ 部分患者响应不足：约30%患者对IL-23抑制剂无应答，可能与遗传背景(如IL23R变异)、肠道微生物组成或疾病阶段(如晚期纤维化)有关。◆ 组织特异性限制：大分子抗体在关节、中枢神经系统等部位的渗透有限，限制其在脊柱关节炎和多发性硬化中的应用。3未来方向◆ 多组学精准分层：通过基因组、微生物组和单细胞转录组分析，识别IL-23依赖性疾病亚型及预测疗效的生物标志物(如HLA-C上游区域变异)。单细胞测序和空间转录组学用于描绘IL-23受体表达细胞的时空分布，揭示细胞异质性对疾病的影响。◆ 新型制剂开发：开发口服IL-23受体拮抗剂(如PTG-200)、高组织渗透性的小分子或双特异性抗体(如V56B2，同时靶向IL-23和TNF)，改善局部药物浓度，拓展至中枢神经系统炎症等适应症。◆ 机制研究：阐明IL-23在维持皮肤、肠道和关节屏障中的作用，探索其在非IMIDs(如肥胖、动脉粥样硬化)中的潜在角色。◆ 早期干预：在疾病早期(如未出现纤维化前)使用IL-23抑制剂，可能更有效抑制TRM细胞，预防慢性化。同时，研究IL-23抑制剂对TRM细胞的清除作用，探索停药后长期缓解的可能性(如GUIDE研究)。抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，小编将持续更新相关内容～参考文献Pastras P, Aggeletopoulou I, Papantoniou K, Triantos C. 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