PIWIL1

Immunocore announces strategic priorities and pipeline expansion ahead of 42nd Annual J.P. Morgan Healthcare Conference presentation Increasing commercial access to KIMMTRAK (tebentafusp-tebn) globally, and pursuing future growth opportunities with two registrational trials in advanced cutaneous melanoma and adjuvant uveal melanoma Multiple clinical readouts expected to start in 2Q 2024 for IMC-F106C (PRAME HLA-A02) from Phase 1/2 clinical trial monotherapy and combination arms; IMC-P115C (PRAME HLA-A02 HLE) and IMC-T119C (PRAME HLA-A24) ImmTAC candidates on track for expected CTA/IND submission in 2024 Submitted clinical trial applications (CTA) for IMC-R117C, a first-in-class ImmTAC targeting PIWIL1 for colorectal and other gastrointestinal cancers Data from IMC-M113V Phase 1 clinical trial in people living with HIV expected in the second half of 2024 Advancing novel TCR bispecific candidates for autoimmune diseases Company to present at 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 10, 2024 at 9:00 AM P.T. / 5:00 PM GMT (OXFORDSHIRE, England & CONSHOHOCKEN, Penn. & ROCKVILLE, Md., US, 05 January, 2024) Immunocore Holdings plc (Nasdaq: IMCR) (“Immunocore” or the “Company”), a commercial-stage biotechnology company pioneering and delivering transformative immunomodulating medicines to radically improve outcomes for patients with cancer, infectious diseases and autoimmune diseases, today sets out its strategic priorities for 2024 and announced the addition of two new pre-clinical candidates for autoimmune diseases to its pipeline. “We continue the global commercial roll out of KIMMTRAK, now launched in 10 countries, and are pursuing future growth opportunities for KIMMTRAK with two registrational trials in advanced cutaneous melanoma and in adjuvant uveal melanoma,” said Bahija Jallal, Chief Executive Officer of Immunocore. “We are advancing our PRAME ImmTAC including our first Phase 3 clinical trial in melanoma and expect to present clinical data from our Phase 1/2 clinical trial in melanoma, ovarian, and lung cancer throughout 2024. Today we add two new autoimmune candidates to our pipeline, expanding the potential of our platform to a third therapeutic area.” Key Strategic Priorities 2024Our strategic priorities are to bring transformative medicines to patients with cancer, infectious diseases, and autoimmune diseases. In 2024, our priorities will be: Growing sales of KIMMTRAK (tebentafusp-tebn) in the United States and globally in patients with HLA-A*02:01-positive metastatic uveal melanoma, and expanding KIMMTRAK beyond its initial approved indication with the registrational trials for advanced (second-line or later) cutaneous melanoma (TEBE-AM) and adjuvant uveal (or ocular) melanoma (ATOM).Advancing our PRAME franchise in multiple solid tumors and broadening the addressable population. Randomization is expected to begin in the first quarter of 2024 in the registrational trial for IMC-F106C in first-line advanced cutaneous melanoma (PRISM-MEL-301), and we expect to present data from the Phase 1/2 clinical trial monotherapy and combination cohorts throughout 2024. We further expect to submit investigational new drug (IND) applications or clinical trial applications (CTA) for IMC-P115C (PRAME HLA-A2 Half-Life-Extended) and IMC-T119C (PRAME HLA-A24) candidates in 2024.Bringing novel ImmTAC candidates to the clinic, leading with IMC-R117C, a first-in-class ImmTAC candidate targeting PIWIL1 with focus on colorectal and gastrointestinal cancers.Evaluating the potential for a functional cure in infectious diseases with lead candidates for human immunodeficiency virus (HIV) and hepatitis B virus (HBV).Initiating CMC manufacturing for the Company’s first two autoimmune candidates – including the first in class, tissue-specific, TCR bispecific PD1 agonist for type 1 diabetes and a novel non-HLA restricted (universal) PD1 agonist for dermatological diseases. KIMMTRAK expansion strategyIn 2024, the Company plans to expand access to KIMMTRAK to more patients in the United States, Europe and globally, as it continues to establish the therapy as standard of care for the first line treatment for metastatic uveal melanoma in countries where it is launched. As of 2023 year-end, KIMMTRAK has been launched in ten countries and is approved in 38 countries. The Company also continues to enroll patients into a Phase 2/3 clinical trial (TEBE-AM) to investigate the potential of KIMMTRAK in advanced cutaneous melanoma, with randomization expected to be completed in the Phase 2 portion during the third quarter of 2024. Topline data from the Phase 2 portion of the trial is expected to be available by the fourth quarter of 2024. In addition, in 2023, the Company signed an agreement for a European Organisation for Research and Treatment of Cancer (EORTC)-sponsored trial to study KIMMTRAK as adjuvant therapy for uveal (or ocular) melanoma (ATOM). The Company anticipates that the EORTC will randomize the first patient in the second half of 2024. PRAME franchise PRISM-MEL301 – First PRAME Phase 3 clinical trial with IMC-F106C in first-line advanced cutaneous melanoma In August 2023, the Company announced plans to start a registrational Phase 3 trial with IMC-F106C in cutaneous melanoma. The trial will randomize patients with HLA-A*02:01-positive, first-line advanced cutaneous melanoma to IMC-F106C + nivolumab versus a control arm of either nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled. The Company plans to randomize the first patient in this trial in the first quarter of 2024. Phase 1/2 clinical trial of IMC-F106C targeting PRAME-A02 in multiple solid tumors In addition to progressing IMC-F106C into a registrational trial in cutaneous melanoma, the Company is continuing to enroll patients in the monotherapy and combination arms of the Phase 1/2 clinical trial across multiple tumor types, including expansion arms for patients with advanced ovarian, non-small cell lung carcinoma, endometrial, and melanoma. In August 2023, the Company provided an updated analysis of the original 18 melanoma patients (initially presented at ESMO in September 2022), which continued to show promising durability of the clinical activity (range of duration of partial response from 6 months to 17 months). The Company expects to report clinical data from the ongoing monotherapy and combination cohorts throughout 2024 including cutaneous melanoma (expected in Q2 2024), ovarian (expected by Q3 2024), and non-small cell lung carcinoma (expected by Q4 2024). IMC-P115C (PRAME-A02 Half-Life Extended) & IMC-T119C (PRAME-A24) The Company is expanding the PRAME franchise with two new PRAME ImmTAC candidates, IMC-P115C (PRAME-A02 HLE) and IMC-T119C (PRAME-A24) for solid tumors, which are both on track for investigational new drug (IND) or clinical trial application (CTA) submissions for IMC-P115C in the second quarter of 2024 and the second half of 2024 for IMC-T119C. IMC-R117C (PIWIL1) for colorectal and other gastrointestinal cancers The Company has leveraged its proprietary peptidomic (ImmSPECT) database to validate a novel target, PIWIL1. PIWIL1 is believed to play a role in tumor progression and is expressed across a range of tumors, including colorectal which is historically insensitive to immune checkpoints, as well as gastrointestinal and pancreatic cancers. PIWIL1 is also reported to be a negative prognostic marker and the Company believes IMC-R117C is the first PIWIL1-targeted immunotherapy. The Company submitted a CTA to regulatory authorities in December 2023, and expects the trial to start this year. Enrolling ImmTAV candidates for a functional cure in infectious diseases The Company continues to enroll people living with HIV in the multiple ascending dose (MAD) part of a Phase 1 clinical trial with IMC-M113V, to identify a safe and tolerable dosing schedule. This study will also test whether IMC-M113V could lead to reduction in the viral reservoir and, after stopping all therapies (antiretroviral therapies and IMC-M113V), delay or prevent HIV rebound (known as functional cure). The MAD part of the trial will enroll up to 28 participants. The Company expects to present a data update from the Phase 1 clinical trial in the second half of 2024. In 2023, the Company amended the design of the ongoing Phase 1 trial with IMC-I109V for people living with HBV to include HBV-positive hepatocellular carcinoma. The Company continues to enroll patients into the trial in 2024. Tissue-specific down modulation of the immune system for autoimmune diseases The Company is expanding its platform into autoimmune with two first in class new bispecific candidates entering the Company’s pipeline. The key differentiator of the ImmTAAI platform is tissue-specific down modulation of the immune system. When tethered to the tissue of interest, the new candidates supress pathogenic T cells via PD1 receptor agonism. The first candidate, IMC-S118AI (PPIxPD1), is targeted specifically to the pancreatic beta-cell and is intended for disease-modifying treatment in type 1 diabetes. IMC-S118AI recognizes a peptide from pre-proinsulin presented by HLA-A*02:01 on beta-cells. The second target is present in the skin and intended to treat inflammatory dermatological diseases. The candidate is an antigen presenting cell (APC) tethered ImmTAAI and is not HLA restricted (e.g. universal for all populations). Preliminary Year-End 2023 cash positionPreliminary unaudited cash and cash equivalents is approximately $443 million USD as of December 31, 2023. 42nd Annual J.P. Morgan Healthcare Conference The Company has updated its corporate presentation to reflect these business and strategic updates. Additionally, the Immunocore management team will discuss these updates during a live and webcast presentation at the 42nd Annual J.P. Morgan Healthcare Conference, on Wednesday January 10, 2024, at 9:00 a.m. Pacific Standard Time (PST). The presentation and webcast will be available in the ‘Investors/Media’ section of Immunocore’s website at www.immunocore.com. A replay of the presentation will be made available for a limited time. ## About ImmTAC® molecules for cancerImmunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune “cold” low mutation rate tumors. About ImmTAV molecules and infectious diseasesImmTAV (Immune mobilising monoclonal TCRs Against Virus) molecules are novel bispecifics that, like ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules, are designed to enable the immune system to recognize and eliminate virally infected cells. Immunocore is advancing clinical candidates to cure patients with HIV and hepatitis B virus (HBV). The Company aims to achieve sustained control of HIV after patients stop anti-retroviral therapy (ART), without the risk of virological relapse or onward transmission. This is known as ‘functional cure’. For the treatment of HBV, the Company aims to achieve sustained loss of circulating viral antigens and markers of viral replication after stopping medication for people living with chronic HBV. About ImmTAAI molecules and autoimmune diseases ImmTAAI (Immune mobilising monoclonal TCRs Against Autoimmune) molecules are novel bispecifics that are designed for tissue-specific down modulation of the immune system. When tethered to the tissue of interest, ImmTAAI candidates supress pathogenic T cells via PD1 receptor agonism. The Company is currently advancing two candidates for autoimmune conditions, including Type 1 Diabetes and inflammatory dermatological diseases. About PRISM-MEL301 – Phase 3 trial with IMC-F106C (PRAMExCD3) in 1L advanced cutaneous melanomaThe Phase 3 registrational trial will randomize patients with previously untreated, HLA-A*02:01-positive, advanced melanoma to IMC-F106C + nivolumab versus nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled. The study will initially randomize to three arms: two IMC-F106C dose regimens (40 mcg and 160 mcg) and control arm and will discontinue one of the IMC-F106C dose regimens after an initial review of the first 60 patients randomized to the two experimental arms (90 patients randomized total). The primary endpoint of the trial is progression free survival (PFS) by blinded independent central review (BICR), with secondary endpoints of overall survival (OS) and overall response rate (ORR). About the IMC-F106C-101 Phase 1/2 TrialIMC-F106C-101 is a first-in-human, Phase 1/2 dose escalation trial in patients with multiple solid tumor cancers including non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), endometrial, ovarian, cutaneous melanoma, and breast cancers. The Phase 1 dose escalation trial was designed to determine the maximum tolerated dose (MTD), as well as to evaluate the safety, preliminary anti-tumor activity and pharmacokinetics of IMC-F106C, a bispecific protein built on Immunocore’s ImmTAC technology, and the Company’s first molecule to target the PRAME antigen. The Company has initiated patient enrollment into four expansion arms in cutaneous melanoma, ovarian, NSCLC, and endometrial carcinomas. The IMC-F106C-101 trial is adaptive and includes the option for Phase 2 expansion, allowing for approximately 100 patients treated per tumor type in the Phase 1 and 2 expansion arms. Dose escalation continues in additional solid tumors as well as plans for combination arms with standards-of-care, including checkpoint inhibitors, chemotherapy, and tebentafusp. About TEBE-AM - Phase 2/3 trial with tebentafusp (gp100xCD3) in second-line or later cutaneous melanomaThe trial is randomizing patients with second-line or later cutaneous melanoma who have progressed on an anti-PD1, received prior ipilimumab and, if applicable, received a BRAF kinase inhibitor. Patients will be randomized to one of three arms including tebentafusp, as monotherapy or in combination with an anti-PD1, and a control arm. The Phase 2 portion of the trial will include 40 patients per arm. About the ATOM Phase 3 trial The EORTC-led Phase 3 clinical trial will include sites in 10 EU countries and the United States and will randomize patients with HLA-A*02:01-positive high-risk primary uveal melanoma after definitive treatment, by surgery or radiotherapy, and no evidence of metastatic disease on imaging. The trial is expected to enroll a total of 290 patients who will be randomized 1:1 to one of two arms: KIMMTRAK as monotherapy or observation. The primary endpoint of the trial is relapse-free survival (RFS), with secondary objectives of overall survival and safety and tolerability of tebentafusp. Exploratory objectives include the comparison of the health-related quality of life between the treatment arms and the evaluation of the role of circulating tumor DNA as a biomarker for the presence of residual disease. About Uveal MelanomaUveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, and up to 50% of people with uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK. About KIMMTRAK®KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumour cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. IMPORTANT SAFETY INFORMATION Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS. Skin Reactions Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions. Elevated Liver Enzymes Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity. Embryo-Fetal ToxicityKIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose. The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate. For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS). About KIMMTRAKConnectImmunocore is committed to helping patients who need KIMMTRAK obtain access via our KIMMTRAKConnect program. The program provides services with dedicated nurse case managers who provide personalized support, including educational resources, financial assistance, and site of care coordination. To learn more, visit KIMMTRAKConnect.com or call 844-775-2273. About ImmunocoreImmunocore is a commercial-stage biotechnology company pioneering the development of a novel class of TCR bispecific immunotherapies called ImmTAX – Immune mobilizing monoclonal TCRs Against X disease – designed to treat a broad range of diseases, including cancer, autoimmune, and infectious disease. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including five clinical stage programs in oncology and infectious disease, advanced pre-clinical programs in autoimmune disease and multiple earlier pre-clinical programs. The Company’s most advanced oncology TCR therapeutic, KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. Forward Looking Statements This press release contains “forward-looking statements” within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “may”, “will”, “believe”, “expect”, “plan”, “anticipate” and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. All statements, other than statements of historical facts, included in this press release are forward-looking statements. These statements include, but are not limited to, statements regarding the commercial performance of KIMMTRAK, including expanded access to KIMMTRAK to more patients in the United States, Europe and globally; the potential benefits and advantages KIMMTRAK will provide for patients; expectations regarding the design, progress, timing, enrollment, scope, expansion, and results of the Company’s existing and planned clinical trials, those of the Company’s collaboration partners or the combined clinical trials with the Company’s collaboration partners; the timing and sufficiency of clinical trial outcomes to support potential approval of any of the Company’s product candidates or those of, or combined with, its collaboration partners; the Company’s goals to develop and commercialize product candidates based on its KIMMTRAK platform alone or with collaboration partners; the expected submission of investigational new drug applications or clinical trial applications; the potential regulatory approval, expected clinical benefits and availability of the Company’s product candidates; the Company’s preliminary unaudited cash and cash equivalents; sales, marketing, manufacturing and distribution requirements; and potential growth opportunities and trends, including in connection with future product launches. Any forward-looking statements are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual events or results to differ materially and adversely from those set forth in or implied by such forward-looking statements, many of which are beyond the Company’s control. These risks and uncertainties include, but are not limited to, the impact of worsening macroeconomic conditions on the Company’s business, financial position, strategy and anticipated milestones, including Immunocore’s ability to conduct ongoing and planned clinical trials; Immunocore’s ability to obtain a clinical supply of current or future product candidates or commercial supply of KIMMTRAK or any future approved products, including as a result of health epidemics or pandemics, war in Ukraine, the conflict between Hamas and Israel, or global geopolitical tension; Immunocore’s ability to obtain and maintain regulatory approval of its product candidates, including KIMMTRAK; Immunocore’s ability and plans in continuing to establish and expand a commercial infrastructure and to successfully launch, market and sell KIMMTRAK and any future approved products; Immunocore’s ability to successfully expand the approved indications for KIMMTRAK or obtain marketing approval for KIMMTRAK in additional geographies in the future; the delay of any current or planned clinical trials, whether due to patient enrollment delays or otherwise; Immunocore’s ability to successfully demonstrate the safety and efficacy of its product candidates and gain approval of its product candidates on a timely basis, if at all; competition with respect to market opportunities; unexpected safety or efficacy data observed during preclinical studies or clinical trials; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials or future regulatory approval; Immunocore’s need for and ability to obtain additional funding, on favorable terms or at all, including as a result of worsening macroeconomic conditions, including changes inflation and interest rates and unfavorable general market conditions, and the impacts thereon of the war in Ukraine, the conflict between Hamas and Israel, and global geopolitical tension; Immunocore’s ability to obtain, maintain and enforce intellectual property protection for KIMMTRAK or any of its product candidates it or its collaborators are developing; and the success of Immunocore’s current and future collaborations, partnerships or licensing arrangements. These and other risks and uncertainties are described in greater detail in the section titled "Risk Factors" in Immunocore’s filings with the Securities and Exchange Commission, including Immunocore’s most recent Annual Report on Form 20-F for the year ended December 31, 2022 filed with the Securities and Exchange Commission on March 1, 2023, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the Company undertakes no duty to update this information, except as required by law. In addition, as the reported cash and cash equivalents in this press release are preliminary, have not been audited and are subject to change pending completion of the Company’s audited financial statements for the year ended December 31, 2023, it is possible that the Company or its independent registered public accounting firm may identify items that require the Company to make adjustments to the amount included in this release, and such changes could be material. Additional information and disclosures would also be required for a more complete understanding of the Company’s financial position and results of operations as of December 31, 2023. CONTACT: Immunocore Sébastien Desprez, Head of CommunicationsT: +44 (0) 7458030732E: sebastien.desprez@immunocore.com Follow on Twitter: @Immunocore Investor Relations Clayton Robertson, Head of Investor RelationsT: +1 215-384-4781E: ir@immunocore.com

Immunocore Reports Third Quarter 2023 Financial Results and Provides Business Update KIMMTRAK net revenues of £49.7 million ($60.7 million) in Q3 2023, maintaining strong momentum in major markets with continued reimbursement expansion globally New Phase 3 clinical trial of KIMMTRAK adjuvant therapy for uveal (or ocular) melanoma (ATOM) in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) Long-term survival for KIMMTRAK in metastatic uveal melanoma demonstrated – published in the New England Journal of Medicine and presented as a mini oral at ESMO Congress 2023 IMC-F106C (PRAME-A02) progressing; data in multiple tumors expected in 1H 2024 and first patient randomized in Phase 3 cutaneous melanoma trial (PRISM-MEL301) in 1Q 2024 Cash and cash equivalents increased to £364 million ($445 million) as of September 30, 2023 (OXFORDSHIRE, England & CONSHOHOCKEN, Penn. & ROCKVILLE, Md., US, 07 November 2023) Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious diseases and autoimmune conditions, today announced its financial results for the third quarter ended September 30, 2023, and provided a business update. “We are proud to have simultaneously published in the New England Journal of Medicine and presented at ESMO 2023 the unprecedented three-year survival follow-up from our pivotal trial of KIMMTRAK in metastatic uveal melanoma,” said Bahija Jallal, Immunocore’s Chief Executive Officer. “We continue to pioneer TCRs by exploring KIMMTRAK in the adjuvant setting with the EORTC-sponsored ATOM Phase 3 clinical trial and progressing the PRAME franchise in multiple solid tumors.” Third Quarter 2023 Highlights (including post-period) KIMMTRAK® KIMMTRAK (tebentafusp-tebn) for metastatic uveal melanoma (mUM) KIMMTRAK is approved in over 35 countries globally. Total net product revenue arising from the sale of KIMMTRAK (or “net sales”) was £49.7 million (or $60.7 million) in the third quarter of 2023, an increase of 9% (or 5% in USD*) compared to the second quarter of 2023, of which £34.5 million (or $42.1 million) was in the United States, £15.0 million (or $18.3 million) in Europe, and £0.2 million (or $0.3 million) in Rest of World. Commercial sales have increased in the United States and European countries, including France, Germany and Italy, during the third quarter. In early August, the Company signed a KIMMTRAK pricing reimbursement agreement with authorities in Germany. Since the beginning of 2023, we have launched KIMMTRAK in Austria, Israel, Italy, Finland, Switzerland and Belgium, and have recently reached price agreements with Canada and Australia. In October, the Company published in the New England Journal of Medicine and presented at the European Society for Medical Oncology (ESMO) 2023 Congress long-term overall survival (OS) data from the KIMMTRAK (tebentafusp-tebn) Phase 3 clinical trial in previously untreated HLA-A*02:01 positive patients with metastatic uveal melanoma. The longest of any randomized trial for metastatic uveal melanoma, the trial demonstrated a three-year OS rate of 27% in the tebentafusp arm, versus 18% in the control arm (investigator’s choice, predominantly [82%] single agent pembrolizumab). In October, the Company signed an agreement for a European Organisation for Research and Treatment of Cancer (EORTC)-sponsored trial to study tebentafusp as adjuvant therapy of uveal (or ocular) melanoma (ATOM). The Phase 3 trial will randomize HLA-A*02:01 positive patients after definitive treatment of high-risk primary uveal melanoma and no evidence of metastatic disease on imaging. Patients will be randomized to one of two arms: KIMMTRAK as monotherapy or observation. The primary endpoint of the trial is relapse-free survival (RFS). The Company anticipates that the EORTC will randomize the first patient in the trial in 2024. The EORTC is a non-profit cancer research organization with a mission to coordinate and conduct international translational and clinical research to improve the standard of cancer treatment for patients. In October, the Company won the prestigious Galenus von Pergamon Prize (the German Prix Galien) for best ‘Orphan Drug’ for KIMMTRAK, adding to the French award for best ‘Medicine in Innovative Therapeutics’ received in 2022. TEBE-AM - Phase 2/3 trial with KIMMTRAK in second-line or later cutaneous melanoma Randomization continues in the Phase 2/3 clinical trial of KIMMTRAK in HLA-A*02:01 positive patients with second-line or later cutaneous melanoma. The trial is randomizing patients with advanced melanoma who have progressed on an anti-PD1, received prior ipilimumab and, if applicable, received a BRAF inhibitor. Patients are being randomized to one of three arms, including KIMMTRAK as monotherapy or in combination with an anti-PD1, and a control arm. The trial has a dual primary endpoint of OS and circulating tumor DNA (ctDNA) reduction. The Company expects to complete randomization of the Phase 2 portion of the trial in the second half of 2024. PRAME franchise PRISM-MEL301 – First PRAME Phase 3 trial with IMC-F106C in first-line cutaneous melanoma In August, the Company announced the planned start of a registrational Phase 3 trial with IMC-F106C in cutaneous melanoma. The trial will randomize patients with HLA-A*02:01 positive, first-line cutaneous melanoma to IMC-F106C + nivolumab versus a control arm of either nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled. The Company plans to randomize the first patient in this trial in the first quarter of 2024. Phase 1/2 IMC-F106C targeting PRAME-A02 in multiple solid tumors In addition to progressing IMC-F106C into a registrational trial in cutaneous melanoma, the Company is continuing to enroll patients in the monotherapy and combination arms of the Phase 1/2 clinical trial across multiple tumor types, including expansion arms for patients with advanced ovarian, non-small cell lung, endometrial, and melanoma cancers. In August, the Company provided an updated analysis of the original 18 melanoma patients (initially presented at ESMO in September 2022), which continues to show promising durability of the clinical activity (range of duration of partial response from 6 months to 17 months). The Company expects to report data from the trial in the first half of 2024. IMC-P115C (PRAME-A02 HLE), IMC-T119C (PRAME-A24) The Company continues to work on expanding the PRAME franchise, with pre-clinical work ongoing for two new PRAME ImmTAC candidates, IMC-P115C (PRAME-A02 HLE) and IMC-T119C (PRAME-A24) for solid tumors, with both on-track for investigational new drug (IND) or clinical trial application (CTA) submission in 2024. Early oncology pipeline IMC-R117C (PIWIL1) The Company remains on-track to submit an IND/CTA in the fourth quarter of 2023 for IMC-R117C, an ImmTAC targeting the PIWIL1 protein for colorectal and other gastrointestinal cancers. The Company believes this is the first PIWIL1-targeted immunotherapy in development. Infectious diseases IMC-M113V and IMC-I109V: aiming for functional cure in HIV and HBV The Company continues to enroll people living with HIV in the multiple ascending dose (MAD) part of a Phase 1 clinical trial with IMC-M113V, to identify a safe and tolerable dosing schedule. This study will also test whether IMC-M113V could lead to reduction in the viral load and, after stopping all therapies (antiretroviral therapies and ImmTAV), delay or prevent HIV rebound (known as functional cure). The MAD part of the trial will enroll up to 28 participants. The Company expects to present a data update in 2024. A Phase 1 clinical trial with IMC-I109V, enrolling people living with HBV, is ongoing and continues to enroll patients in the single ascending dose portion of the trial. In August, the Company announced that the multiple dose portion of the trial has been amended to include patients with HBV-positive hepatocellular carcinoma. Corporate Updates The Company appointed John Goll as Senior Vice President (SVP), Finance and Chief Accounting Officer. Prior to joining Immunocore, he served as the SVP, Chief Accounting Officer at Insmed. Additionally, the Company appointed John Trainer as SVP, Chief Operating Officer. Prior to joining the Company, John served as the Chief Financial Officer at NexImmune. Financial Results Total net product revenue arising from the sale of KIMMTRAK was £49.7 million ($60.7 million) and £137.3 million ($167.7 million) in the three and nine months ended September 30, 2023, respectively, of which £34.5 million ($42.1 million) and £96.9 million ($118.3 million) was in the United States, £15.0 million ($18.3 million) and £39.5 million ($48.3 million) was in Europe, and £0.2 million ($0.3 million) and £0.9 million ($1.1 million) was in Rest of World. For the three and nine months ended September 30, 2022, the Company recorded total net product and pre-product revenue of £36.3 million and £74.5 million, respectively. For the three and nine months ended September 30, 2023, the Company’s research and development expenses were £31.7 million ($38.7 million) and £88.9 million ($108.6 million), respectively, as compared to £23.3 million and £62.0 million for the three and nine months ended September 30, 2022, respectively. For the three and nine months ended September 30, 2023, the selling and administrative expenses were £20.3 million ($24.8 million) and £87.5 million ($106.8 million), respectively, compared to £11.7 million and £50.6 million for the three and nine months ended September 30, 2022, respectively. Basic and diluted profit per share for the three months ended September 30, 2023 was £0.04 (or $0.05 and $0.04, respectively), as compared to basic profit per share of £0.13 and diluted profit per share of £0.12 for the three months ended September 30, 2022. Basic and diluted loss per share for the nine months ended September 30, 2023 was £0.59 (or $0.72), compared to a basic and diluted loss per share of £0.36 for the nine months ended September 30, 2022. Cash and cash equivalents were £364.0 million ($444.5 million) as of September 30, 2023, compared to £332.5 million as of December 31, 2022. * The Company maintains its books and records in pounds sterling. For the convenience of the reader, the Company has translated pound sterling amounts as of and for the period ended September 30, 2023 into U.S. dollars at a rate of £1.00 to $1.2214. Comparisons to the three months ended June 30, 2023 are based on previously reported U.S. dollar amounts, which applied a convenience rate of £1.00 to $1.2709. ## About the ATOM Phase 3 trial The EORTC-led Phase 3 clinical trial will include sites in 10 EU countries and the United States and will randomize patients with HLA-A*02:01 positive high-risk primary uveal melanoma after definitive treatment, by surgery or radiotherapy, and no evidence of metastatic disease on imaging. The trial is expected to enroll a total of 290 patients who will be randomized 1:1 to one of two arms: KIMMTRAK as monotherapy or observation. The primary endpoint of the trial is relapse-free survival (RFS), with secondary objectives of overall survival and safety and tolerability of tebentafusp. Exploratory objectives include the comparison of the health-related quality of life between the treatment arms and the evaluation of the role of circulating tumor DNA as a biomarker for the presence of residual disease. About TEBE-AM - Phase 2/3 trial with tebentafusp (gp100xCD3) in second-line or later cutaneous melanoma The trial is randomizing patients with second-line or later cutaneous melanoma who have progressed on an anti-PD1, received prior ipilimumab and, if applicable, received a BRAF kinase inhibitor. Patients will be randomized to one of three arms including tebentafusp, as monotherapy or in combination with an anti-PD1, and a control arm. The Phase 2 portion of the trial will include 40 patients per arm. About PRISM-MEL301 – Phase 3 trial with IMC-F106C (PRAMExCD3) in 1L advanced cutaneous melanoma The Phase 3 registrational trial will randomize patients with previously untreated, HLA-A*02:01 positive, advanced melanoma to IMC-F106C + nivolumab versus nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled. The study will initially randomize to three arms: two F106C dose regimens (40 mcg and 160 mcg) and control arm and will discontinue one of the F106C dose regimens after an initial review of the first 60 patients randomized to the two experimental arms (90 patients randomized total). The primary endpoint of the trial is progression free survival (PFS) by blinded independent central review (BICR), with secondary endpoints of overall survival (OS) and overall response rate (ORR). About ImmTAV molecules and infectious diseases ImmTAV (Immune mobilizing monoclonal TCRs Against Virus) molecules are novel bispecific molecules that, like ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules, are designed to enable the immune system to recognize and eliminate virally infected cells. Immunocore is advancing clinical candidates to cure patients with HIV and HBV. The Company aims to achieve a reduction in viral reservoirs to enable sustained control of HIV after stopping antiretroviral therapy (ART), without the risk of virological relapse or onward transmission. This is known as ‘functional cure’. For the treatment of HBV, the Company aims to achieve sustained loss of circulating viral antigens and markers of viral replication after stopping medication for people living with chronic hepatitis B. About Uveal Melanoma Uveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, and up to 50% of people with uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK. About KIMMTRAK® KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. IMPORTANT SAFETY INFORMATION Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS. Skin Reactions Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions. Elevated Liver Enzymes Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity. Embryo-Fetal Toxicity KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose. The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate. For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS). About KIMMTRAKConnect Immunocore is committed to helping patients who need KIMMTRAK obtain access via our KIMMTRAKConnect program. The program provides services with dedicated nurse case managers who provide personalized support, including educational resources, financial assistance, and site of care coordination. To learn more, visit KIMMTRAKConnect.com or call 844-775-2273. About Immunocore Immunocore is a commercial-stage biotechnology company pioneering the development of a novel class of TCR bispecific immunotherapies called ImmTAX – Immune mobilizing monoclonal TCRs Against X disease – designed to treat a broad range of diseases, including cancer, autoimmune, and infectious disease. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including five clinical stage programs in oncology and infectious disease, advanced pre-clinical programs in autoimmune disease and multiple earlier pre-clinical programs. The Company’s most advanced oncology TCR therapeutic, KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. Forward Looking Statements This press release contains “forward-looking statements” within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “may”, “will”, “believe”, “expect”, “plan”, “anticipate” and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. All statements, other than statements of historical facts, included in this press release are forward-looking statements. These statements include, but are not limited to, statements regarding the commercial performance of KIMMTRAK including planned launches in additional countries including Canada; the ability to translate a pricing agreement into a success launch; the potential benefits and advantages KIMMTRAK will provide for patients; the estimated market share of KIMMTRAK; the benefits of the Company’s collaboration with EORTC; the risk that the Company may not realize the anticipated benefits of its collaboration with EORTC; uncertainties relating to regulatory applications and related filing and approval timelines for tebentafusp as a treatment for positive high-risk primary uveal melanoma or other programs subject of the collaboration, including the risk that FDA may not approve any such programs on the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on its use; the estimated market size and patient population for KIMMTRAK and the Company’s other product candidates; expectations regarding the design, progress, timing, enrollment, scope, expansion, and results of the Company’s existing and planned clinical trials, those of the Company’s collaboration partners or the combined clinical trials with the Company’s collaboration partners; the timing and sufficiency of clinical trial outcomes to support potential approval of any of the Company’s product candidates or those of, or combined with, its collaboration partners, the Company’s goals to develop and commercialize product candidates based on its KIMMTRAK platform alone or with collaboration partners; the expected submission of investigational new drug applications or clinical trial applications; the potential regulatory approval, expected clinical benefits and availability of Immunocore’s product candidates; market competition; sales, marketing, manufacturing and distribution requirements; and potential growth opportunities and trends, including in connection with product launches in future quarters. Any forward-looking statements are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual events or results to differ materially and adversely from those set forth in or implied by such forward-looking statements, many of which are beyond the Company’s control. These risks and uncertainties include, but are not limited to, the impact of worsening macroeconomic conditions on the Company’s business, financial position, strategy and anticipated milestones, including Immunocore’s ability to conduct ongoing and planned clinical trials; Immunocore’s ability to obtain a clinical supply of current or future product candidates or commercial supply of KIMMTRAK or any future approved products, including as a result of health epidemics or pandemics, war in Ukraine, the conflict between Hamas and Israel, or global geopolitical tension; Immunocore’s ability to obtain and maintain regulatory approval of its product candidates, including KIMMTRAK; Immunocore’s ability and plans in continuing to establish and expand a commercial infrastructure and to successfully launch, market and sell KIMMTRAK and any future approved products; Immunocore’s ability to successfully expand the approved indications for KIMMTRAK or obtain marketing approval for KIMMTRAK in additional geographies in the future; the delay of any current or planned clinical trials, whether due to patient enrollment delays or otherwise; Immunocore’s ability to successfully demonstrate the safety and efficacy of its product candidates and gain approval of its product candidates on a timely basis, if at all; competition with respect to market opportunities; unexpected safety or efficacy data observed during preclinical studies or clinical trials; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials or future regulatory approval; Immunocore’s need for and ability to obtain additional funding, on favorable terms or at all, including as a result of worsening macroeconomic conditions, including changes inflation and interest rates and unfavorable general market conditions, and the impacts thereon of the war in Ukraine, the conflict between Hamas and Israel, and global geopolitical tension; Immunocore’s ability to obtain, maintain and enforce intellectual property protection for KIMMTRAK or any of its product candidates it or its collaborators are developing; and the success of Immunocore’s current and future collaborations, partnerships or licensing arrangements. These and other risks and uncertainties are described in greater detail in the section titled "Risk Factors" in Immunocore’s filings with the Securities and Exchange Commission, including Immunocore’s most recent Annual Report on Form 20-F for the year ended December 31, 2022 filed with the Securities and Exchange Commission on March 1, 2023, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the Company undertakes no duty to update this information, except as required by law. CONTACT: ImmunocoreSébastien Desprez, Head of CommunicationsT: +44 (0) 7458030732E: sebastien.desprez@immunocore.com Follow on Twitter: @Immunocore Investor Relations Clayton Robertson / Morgan Warenius T: +1 215-384-4781E: ir@immunocore.com Unaudited Condensed Consolidated Statements of Profit / (Loss) Comparison of the Three Months Ended September 30, 2023 and 2022 Three Months Ended September 30, 2023 2022 $’000 £’000 £’000Product revenue, net 60,727 49,719 33,252Pre-product, revenue, net — — 3,051Collaboration revenue 2,161 1,769 4,896Total revenue 62,888 51,488 41,199 Cost of product revenue (269) (220) (63)Research and development expenses (38,693) (31,679) (23,301)Selling and administrative expenses (24,780) (20,288) (11,663)Operating (loss) / profit (854) (699) 6,172Finance income 4,997 4,091 597Finance costs (1,993) (1,632) (1,785)Net finance income / (costs) 3,004 2,459 (1,188)Profit before taxes 2,150 1,760 4,984Income tax credit 176 144 1,244Profit for the period 2,326 1,904 6,228 Basic profit per share - $ / £ $0.05 £0.04 £0.13Diluted profit per share - $ / £ $0.04 £0.04 £0.12 Basic weighted average number of shares 49,134,037 46,998,420Diluted weighted average number of shares 54,158,967 51,443,276 Nine Months Ended September 30, 2023 2022 $’000 £’000 £’000Product revenue, net 167,680 137,285 64,926Pre-product, revenue, net — — 9,588Collaboration revenue 7,949 6,508 21,161Total revenue 175,629 143,793 95,675 Cost of product revenue (1,568) (1,284) (345)Research and development expenses (108,576) (88,895) (62,032)Selling and administrative expenses (106,840) (87,473) (50,579)Operating loss (41,355) (33,859) (17,281)Finance income 12,274 10,049 725Finance costs (5,883) (4,817) (4,515)Net finance income / (costs) 6,391 5,232 (3,790)Loss before taxes (34,964) (28,627) (21,071)Income tax (charge) / credit (297) (243) 5,050Loss for the period (35,261) (28,870) (16,021)Basic and diluted loss per share - $ / £ (0.72) (0.59) (0.36) Weighted average number of shares 48,671,732 44,944,827 Condensed Consolidated Statements of Financial Position at September 30,2023£’000 December 31,2022£’000Non-current assets Property, plant and equipment 8,025 6,472Intangible assets 1,589 410Right of use assets 25,832 25,173Other non-current assets 8,846 7,342Deferred tax asset 4,135 4,240Total non-current assets 48,427 43,637Current assets Inventory 1,857 943Trade and other receivables 49,880 46,711Tax receivable — 11,688Cash and cash equivalents 363,955 332,539Total current assets 415,692 391,881Total assets 464,119 435,518Equity Share capital 99 97Share premium 146,205 123,751Foreign currency translation reserve (4,266) (3,097)Other reserves 337,847 337,847Share-based payment reserve 101,781 81,411Accumulated deficit (290,123) (261,253)Total equity 291,543 278,756Non-current liabilities Non-current accruals 2,531 1,479Interest-bearing loans and borrowings 38,484 39,500Deferred revenue 4,331 4,331Lease liabilities 29,469 28,248Provisions 153 114Total non-current liabilities 74,968 73,672Current liabilities Trade and other payables 93,135 75,076Corporation tax liability 367 —Interest-bearing loans and borrowings 1,024 —Deferred revenue 1,602 6,408Lease liabilities 1,445 1,555Provisions 35 51Total current liabilities 97,608 83,090Total liabilities 172,576 156,762Total equity and liabilities 464,119 435,518 Issued number of ordinary shares 49,438,256 48,088,346 Condensed Consolidated Statement of Cash Flows for Each Period Presented: Nine Months Ended September 30, 2023 2023 2022 $’000 £’000 £’000 Cash and cash equivalents at beginning of year 406,163 332,539 237,886Net cash flows from / (used in) operating activities 14,069 11,519 (31,923)Net cash flows from / (used in) investing activities 5,439 4,453 (139)Net cash flows from financing activities 19,862 16,262 115,645Net foreign exchange difference on cash held (999) (818) 25,720Cash and cash equivalents at end of period 444,534 363,955 347,189

针对上述科学问题，科研人员分别制备和获得了四种PIWI蛋白的特异性抗体，结合超分辨共聚焦显微技术，全面分析了四种PIWI亚家族蛋白在金黄地鼠精子发生、卵子发生和早期胚胎发育中的时空表达特征 《自然-通讯》（Nature Communications）在线发表了中国科学院分子细胞科学卓越创新中心吴立刚研究组与南京医科大学李建民研究组合作完成的最新研究成果（The non-redundant functions of PIWI family proteins in gametogenesis in golden hamsters）。该研究以金黄地鼠（Mesocricetus auratus，golden hamster）为动物模型，全面揭示了PIWI家族成员及其结合的piRNA在配子发生和早期胚胎发生中非冗余的调控功能，为研究哺乳动物piRNA功能奠定了重要基础。 piRNA（PIWI-interacting RNA）是一类生殖细胞特异表达的非编码小RNA，与PIWI蛋白形成效应复合体，参与转座子沉默和基因表达调控，在配子发生和受精卵发育过程中发挥广泛而重要的功能。以往对哺乳动物PIWI/piRNA的功能认识主要基于小鼠模型。然而，研究组的前期研究表明小鼠卵细胞中非编码小RNA的组成在哺乳动物中不具有广泛代表性，并首次在人和食蟹猴卵细胞中发现新的piRNA家族成员os-piRNA。近期，包括该研究组在内的三项独立研究表明，piRNA通路重要作用蛋白PIWIL1和MOV10L1（RNA解旋酶）的缺失均可导致金黄地鼠雌雄不育，与小鼠中表型存在明显差别。上述研究证明了小鼠不是研究哺乳动物雌性生殖细胞发育中piRNA功能的最佳动物模型，以往通过小鼠建立的哺乳动物piRNA经典结论需要在更加具有代表性的金黄地鼠中重新研究或加以确认。 针对上述科学问题，科研人员分别制备和获得了四种PIWI蛋白的特异性抗体，结合超分辨共聚焦显微技术，全面分析了四种PIWI亚家族蛋白在金黄地鼠精子发生、卵子发生和早期胚胎发育中的时空表达特征，并结合高通量测序技术细致地描绘了不同发育时期中PIWI蛋白所结合的piRNA表达谱。进一步，研究利用CRISPR技术分别构建了四种PIWI缺失的金黄地鼠突变系，探讨了不同PIWI蛋白突变所引发的生殖缺陷表型。结果表明，PIWIL1同时在雌性和雄性生殖细胞及早期胚胎中高表达，主要结合29-30 nt piRNA，突变后导致雌雄均不可育：突变的生精细胞在进入双线期前发生大量死亡，部分可进入双线期的生精细胞随后发育停滞，而突变的卵母细胞可正常发育，但受精后胚胎发育停滞于2细胞时期。PIWIL2和PIWIL4主要在生精细胞中表达，但两者表达存在明显的时期特异性，且分别结合27 nt或28 nt piRNA。PIWIL2或PIWIL4突变后生精过程严重受阻，大量精原细胞凋亡，造成雄性不育。PIWIL3高表达于卵母细胞和早期胚胎中，结合19 nt的os-piRNA，突变后卵母细胞发育正常，但受精后的胚胎发育迟缓，且大部分在发育过程中停滞或凋亡，最终导致生育能力显著下降。 研究发现，PIWI蛋白功能存在明确的分工但又紧密联系。在卵母细胞发育中，PIWIL1/piRNA可以代偿PIWIL3/piRNA活性，抑制以LINE/L1和LTR/ERVK为主的活跃转座子的表达，反之则不然。而在生精细胞发育过程中，PIWIL4入核功能及其相关piRNA的加工依赖于PIWIL2，两者协同完成转座子的转录水平和转录后水平沉默。 综上，本研究使用更具代表性的金黄地鼠作为模型，全面绘制了PIWI家族各个成员在配子发生和早期胚胎发育中的时空表达谱，构建并比较了四种PIWI突变体的生育表型和分子表型，发现了四种PIWI蛋白在配子发生和早期胚胎发育中具有非冗余的调控作用，为piRNA通路异常与人类生殖相关疾病的诊治奠定了重要理论基础、提供了动物模型。 研究工作得到国家自然科学基金委员会、科学技术部、中国科学院、上海市和江苏省的资助。研究工作获得分子细胞卓越中心实验动物技术平台和信息化管理团队的支持。南京医科大学科研人员参与研究。