Tebentafusp

Immunocore reports first quarter financial results and provides a business update KIMMTRAK® (tebentafusp-tebn) net revenues of $93.9 million in Q1 2025, growing by 33% year-over-year On track for Phase 3 TEBE-AM trial to complete enrollment in 1H 2026 On track for dose selection in Phase 3 PRISM-MEL-301 trial in 2H 2025 Initial multiple ascending dose data for HIV functional cure candidate presented during oral session at CROI 2025; dose escalation ongoing Cash, cash equivalents and marketable securities of $837 million as of March 31, 2025 (OXFORDSHIRE, England & CONSHOHOCKEN, Penn. & GAITHERSBURG, Md., US, May 7, 2025) 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 announced its financial results for the first quarter ended March 31, 2025, and provided a business update. "We are thrilled to have achieved strong revenue performance in Q1, marked by year-over-year growth of 33%. This reflects our unwavering dedication to making KIMMTRAK accessible to patients who need it," said Bahija Jallal, Chief Executive Officer of Immunocore. "In R&D, we continue to be laser-focused on execution in our oncology franchise with three ongoing Phase 3 trials and a promising early pipeline. We are also excited to have presented the initial MAD data at CROI from our ongoing HIV trial, which, together with our progress in autoimmune, underscores the breadth of our platform." First Quarter 2025 Highlights (including post-period) Financial ResultsTotal net product revenue (or “net sales”) arising from the sales of KIMMTRAK® (tebentafusp) was $93.9 million in the first quarter of 2025, an increase of 33% over the first quarter of 2024, of which $56.6 million was generated in the United States, $32.8 million in Europe and $4.5 million in international regions. Research & development expenses for the three months ended March 31, 2025, were $56.5 million, compared to $57.5 million for the same period in 2024. Selling, general and administrative (SG&A) expenses for the three months ended March 31, 2025, were $40.2 million, compared to $39.3 million in the same period in 2024. Net income for the first quarter of 2025 was $5.0 million compared to a net loss of $24.4 million in the same period in 2024. The first quarter basic and diluted income/(loss) per share was $0.10, compared to $(0.49) for the first quarter of 2024. Cash, cash equivalents and marketable securities at March 31, 2025, were $837.0 million. KIMMTRAKThe Company’s lead product, KIMMTRAK® (tebentafusp), is approved in 39 countries and has been launched in 26 countries globally to date for HLA-A*02:01 positive people with metastatic uveal melanoma (mUM). KIMMTRAK continues to be the standard of care in most markets where it is launched. The Company sees three key growth areas for KIMMTRAK including continued global expansion in mUM, the potential expansion into 2L+ advanced cutaneous melanoma (CM), and the potential expansion into adjuvant uveal melanoma. Metastatic uveal melanoma In the first quarter of 2025, KIMMTRAK net product sales were $93.9 million.Now launched in two additional countries for a total of 26 globally.13% year-over-year growth in the United States, with demand continuing to grow as outreach extends into the community setting.Growth in Europe and in international regions driven by increased demand, new country launches, and completion of price negotiations in France and Germany. 2L+ advanced cutaneous melanoma The Company is currently enrolling the TEBE-AM registrational Phase 3 trial and expects to complete enrollment in the first half of 2026.The Phase 3 trial is enrolling three arms: tebentafusp monotherapy, tebentafusp in combination with pembrolizumab, and a control (investigator's choice of therapy including options such as investigator’s choice of clinical trials, chemotherapy, or retreatment with anti-PD1 or BRAF therapy).There is great unmet need in second- and later-line cutaneous melanoma, with no therapy having shown an Overall Survival (OS) improvement post checkpoint inhibitors in a randomized clinical trial. The Company estimates that there is a potential to address up to 4,000 previously treated advanced CM patients. Adjuvant uveal (or ocular) melanoma The European Organisation for Research and Treatment of Cancer (EORTC) is enrolling patients in the Phase 3 Adjuvant Trial in Ocular Melanoma (ATOM).The Company estimates that the HLA-A*02:01 high-risk adjuvant uveal melanoma patient population could be up to 1,200 patients. PRAME portfolio Brenetafusp is the Company’s lead PRAME-A02 ImmTAC bispecific candidate. Brenetafusp is being evaluated in combination with nivolumab in a Phase 3 registrational trial (PRISM-MEL-301) in patients with first-line, advanced cutaneous melanoma, and in a Phase 1/2 clinical trial as monotherapy and in combination across multiple tumor types, including ovarian cancer and non-small cell lung cancer (NSCLC). PRISM-MEL-301 – First PRAME Phase 3 clinical trial with brenetafusp in first-line advanced cutaneous melanoma The Company is enrolling patients in the registrational Phase 3 clinical trial evaluating brenetafusp + nivolumab versus a control arm of either nivolumab or nivolumab + relatlimab for HLA-A*02:01 positive patients with first-line, advanced or metastatic cutaneous melanoma.The trial is currently randomizing to three arms: two brenetafusp dose regimens (40 mcg and 160 mcg) and a control arm. The Company is on track for selection of the go-forward brenetafusp dose in the second half of 2025; this analysis will be conducted by an IDMC.Despite approved therapies, there remains a need for improved progression-free survival and overall survival, and there is the potential to address an estimated 10,000 patients. Phase 1/2 clinical trial of brenetafusp in multiple solid tumors The Company continues to evaluate brenetafusp in a Phase 1/2 trial in combination with non-platinum chemotherapies in platinum-resistant ovarian cancer (PROC) and with bevacizumab or with platinum chemotherapy in earlier lines of platinum-sensitive ovarian cancer (PSOC). In the same trial, the Company continues signal detection in metastatic non-small cell lung cancer (NSCLC) cohorts, including brenetafusp in combination with docetaxel and with osimertinib in earlier-line NSCLC.The Company estimates that, across all solid tumors, the annual number of patients worldwide who test positive for HLA-A*02:01 and can potentially benefit from this program is up to 150,000. IMC-P115C (PRAME-A02 Half-Life Extended) & IMC-T119C (PRAME-A24) The Company is enrolling patients in the Phase 1 dose escalation trial, in multiple solid tumors, with IMC-P115C.IMC-P115C is the Company’s first half-life extended ImmTAC therapy – targeting the same PRAME peptide and with the same CD3 effector and TCR specificity as brenetafusp. It is designed to improve patient convenience by reducing the frequency of treatment administration. IMC-R117C (PIWIL1) for colorectal and other gastrointestinal cancers The Company is enrolling patients in the Phase 1/2 dose escalation trial evaluating IMC-R117C in HLA-A*02:01 positive patients with advanced solid tumors, including colorectal cancer, as a single agent and in combination with standards of care.PIWIL1 is believed to play a role in tumor progression and is expressed across a range of tumors, including colorectal cancer. ImmTAV candidates for a functional cure in infectious diseasesThe Company’s bispecific TCR technology platform has the potential to offer a new approach for the treatment of certain chronic infections and aims to eliminate evidence of remaining virus in circulation after the patient stops taking medication - known as a "functional cure." Two investigational candidates are in Phase 1 or Phase 1/2 trials for people living with human immunodeficiency virus (HIV) and people with chronic hepatitis B infection (HBV). Phase 1/2 trial of IMC-M113V (Gag-A02) for people living with HIV The Company presented data from the initial multiple ascending dose (MAD) portion of the Phase 1/2 dose escalation trial, including 16 people living with HIV (PLWH), at the 2025 Conference on Retroviruses and Opportunistic Infections (CROI).All doses were well tolerated and no serious adverse events or dose limiting toxicities were observed. In the 15 evaluable PLWH, delayed viral rebound and/or viremia control at any point during the analytical treatment interruption (ATI) was observed in 0 of 5 PLWH at 60 mcg, 1 of 5 at 120 mcg, and 2 of 5 at 300 mcg.The 3 PLWH with evidence of viral control had a viral load of approximately 200 copies/mL at week 8. The historical rate for this observation is 5%1. Furthermore, 2 of these 3 PLWH remained off ART for the entire 12-week ATI period that was pre-specified in the protocol.Patient enrollment continues at higher doses in the multiple ascending dose part of the Phase 1/2 clinical trial to identify a safe and tolerable dose. Phase 1 trial of IMC-I109V (Envelope-A02) for people living with HBV or HBV-positive hepatocellular carcinoma The Company plans to report data from the single ascending dose portion of the trial in the second half of 2025. Tissue-specific down modulation of the immune system for autoimmune diseasesThe key differentiator of the ImmTAAI platform is tissue-specific, down modulation of the immune system, as the candidates suppress pathogenic T cells via PD1 receptor agonism only when tethered to the target tissue. IMC-S118AI (PPI-A02) for type 1 diabetes The Company is on track to file a CTA or investigational new drug application (IND) for IMC-S118AI (PPI x PD1) in the second half of 2025.IMC-S118AI is targeted specifically to the pancreatic beta-cell and intended as a disease-modifying treatment in type 1 diabetes. IMC-S118AI recognizes a peptide from pre-pro-insulin protein that is presented by HLA-A02 on beta cells and has a PD1 agonist effector arm. IMC-U120AI (CD1a) for atopic dermatitis as the initial indication - first universal program The Company plans to file a CTA/IND for IMC-U120AI (CD1a x PD1) in 2026.IMC-U120AI is a non-HLA-restricted (i.e. universal for all populations) CD1a-tethered PD1 agonist ImmTAAI therapy. IMC-U120AI has a dual mechanism of action: blocking CD1a (which presents lipids) from activating CD1a-specific T cells and preventing HLA Class I/II (which presents peptides) from activating T cells via PD1 agonism on the T cell. Financial ResultsBasic and diluted income per share was $0.10 for the quarter ended March 31, 2025, as compared to a basic and diluted loss per share of ($0.49) for the same period in 2024. Net income for the quarter ended March 31, 2025, was $5.0 million, as compared to a net loss of $(24.4) million for the same period in 2024. For the first quarter ended March 31, 2025, the Company generated net product sales of $93.9 million compared to $70.3 million for the same period in 2024, due to sales of KIMMTRAK, of which $56.6 million was in the United States, $32.8 million (including one-time favorable revenue adjustments recorded upon completion of price negotiations in France and Germany of $6.0M) was in Europe, and $4.5 million was in the international regions. The increase in net product sales was due to global country expansion and increased sales volume in the United States, as we continued our commercialization efforts. For the first quarter ended March 31, 2025, research and development (R&D) expenses were $56.5 million compared to $57.5 million for the same period in 2024. For the quarter ended March 31, 2025, SG&A expenses were $40.2 million compared to $39.3 million for the same period in 2024. Cash, cash equivalents and marketable securities were $837.0 million as of March 31, 2025, as compared to $820.4 million as of December 31, 2024. ## About ImmTAC® molecules for cancer Immunocore’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 diseases ImmTAV (Immune mobilising monoclonal TCRs Against Virus) molecules are novel bispecifics that 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 mobilizing monoclonal TCRs Against AutoImmune disease) 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 suppress 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 (NCT06112314) – Phase 3 trial with brenetafusp (IMC-F106C, PRAME-A02) in 1L advanced cutaneous melanoma The Phase 3 registrational trial is randomizing HLA-A*02:01-positive patients with previously untreated advanced melanoma to brenetafusp + nivolumab versus nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled. The trial will initially randomize to three arms: two brenetafusp dose regimens (40 mcg and 160 mcg) and control arm. One of the two brenetafusp dose regimens will be discontinued 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 trial IMC-F106C-101 is a first-in-human, Phase 1/2 dose escalation trial in patients with multiple solid tumors including non-small cell lung and ovarian 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 (brenetafusp), a bispecific protein built on Immunocore’s ImmTAC technology, and the Company’s first molecule to target the PRAME antigen. The Company is currently focusing on enrolling patients in combination arms with standards-of-care across multiple tumor types. 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 advanced cutaneous melanoma who have progressed on an anti-PD1, received prior ipilimumab and, if applicable, received a BRAF kinase inhibitor. Patients are randomized to one of three arms including tebentafusp, as monotherapy or in combination with an anti-PD1, and a control arm. The primary endpoint is overall survival. 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 is randomizing HLA-A*02:01-positive patients with 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: tebentafusp 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 (ctDNA) as a biomarker for the presence of residual disease. 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 Cutaneous Melanoma Cutaneous melanoma (CM) is the most common form of melanoma. It is the most aggressive skin carcinoma and is associated with the vast majority of skin cancer-related mortality. The majority of patients with CM are diagnosed before metastasis but survival remains poor for the large proportion of patients with metastatic disease. Despite recent progress in advanced melanoma therapy, there is still an unmet need for new therapies that improve first-line response rates and duration of response as well as for patients who are refractory to first-line treatments. 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 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 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 diseases and infectious diseases. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including numerous active clinical and pre-clinical programs​ in oncology, infectious diseases, and autoimmune diseases. 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”, “aim”, “continue”, “target” 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 Company’s ability to advance its clinical pipeline; the key growth areas for KIMMTRAK, including continued global expansion in mUM, the potential expansion into 2L+ advanced cutaneous melanoma, and into adjuvant uveal melanoma; the commercial performance of KIMMTRAK; the potential benefits and advantages that KIMMTRAK will provide for patients; expectations regarding the estimated size of the patient populations for the Company’s product candidates; expectations regarding the design, progress, timing, enrollment, randomization, scope, expansion, funding, 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 clinical trial applications; and the potential regulatory approval, expected clinical benefits and availability of the Company’s product candidates. 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; 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 in inflation and interest rates and unfavorable general market conditions, and the impacts thereon of the war in Ukraine, the conflict in the Middle East, 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 10-K for the year ended December 31, 2024 filed with the Securities and Exchange Commission on February 26, 2025, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the SEC. 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 Information Immunocore Sébastien Desprez, VP CommunicationsT: +44 (0) 7458030732E: sebastien.desprez@immunocore.comFollow Immunocore on LinkedIn: @Immunocore Investor Relations Clayton Robertson / Morgan WareniusT: +1 (215) 384-4781E: ir@immunocore.com Immunocore Holdings plcCondensed Consolidated Statement of OperationsQuarter Ended March 31, 2025 and 2024 (In thousands, except share and per share data)(Unaudited) Quarter Ended March 31, 2025March 31, 2024 Revenue from sale of therapies, net$93,881$70,342 Collaboration revenue—160 Total revenue93,88170,502 Cost of revenue from sale of therapies(831)(246) Research and development expenses(56,468)(57,459) Selling, general, & administrative expenses(40,198)(39,287) Loss from operations(3,616)(26,490) Interest income4,1768,246 Interest expense(3,025)(3,239) Foreign currency gain (loss)3,080(2,406) Other income (expense), net5,469(190) Net income (loss) before income taxes6,084 (24,079) Income tax expense(1,061)(357) Net income (loss)$5,023$(24,436) Basic net income (loss) per share$0.10$(0.49) Basic weighted-average number of shares outstanding50,086,68449,877,218 Diluted net income (loss) per share$0.10$(0.49) Diluted weighted-average number of shares outstanding51,949,79849,877,218 Immunocore Holdings plcCondensed Consolidated Balance SheetsAs of (In thousands)(Unaudited) March 31, 2025December 31, 2024ASSETS Current assets Cash and cash equivalents$476,845$455,731Marketable securities360,185364,645Accounts receivable, net63,09463,009Prepaid expenses and other current assets41,69741,033Inventory, net6,8045,446Total current assets948,625929,864Property and equipment, net9,77010,092Operating lease right of use assets, net38,12637,643Deferred tax assets, net14,35514,790Other non-current assets17,13217,117Total assets$1,028,008$1,009,506 Liabilities and shareholders’ equity Current liabilities Accounts payable$29,105$25,100Accrued expenses and other current liabilities118,341185,534Operating lease liabilities, current1,7171,547Total current liabilities149,163212,181Accrued expenses, non-current62,476—Deferred revenue, non-current5,6125,434Operating lease liabilities, non-current40,74840,162Interest-bearing loans and borrowings391,530391,013Total liabilities$649,529$648,790 Shareholders' equity Ordinary shares135135Deferred shares11Additional paid-in capital1,202,1711,190,104Accumulated deficit(790,738)(795,761)Accumulated other comprehensive loss(33,090)(33,763)Total shareholders' equity378,479360,716Total liabilities and shareholders' equity$1,028,008$1,009,506 Immunocore Holdings plcSummary Condensed Consolidated Statements of Cash FlowsFor the Quarter Ended March 31, (In thousands)(Unaudited) 20252024 Cash and cash equivalents at beginning of period$455,731$442,626Net cash provided by (used in) operating activities435(4,587)Net cash provided by (used in) investing activities9,702(430)Net cash provided by financing activities2,551396,012Net foreign exchange difference on cash held8,426(800)Cash and cash equivalents at end of period$476,845$832,821 1 Gunst, J.D., Gohil, J., Li, J.Z. et al. Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies. Nat Commun 16, 906 (2025).

-01-引言迄今为止，与传统的抗癌治疗策略相比，免疫治疗被认为是最有前景的全身性肿瘤治疗方法，其中，单克隆抗体因其特异性靶向分子的能力，已成为癌症治疗中一种关键而有效的治疗方式。然而，由于肿瘤复杂的疾病发病机制，针对单一靶点的单克隆抗体往往不足以表现出足够的治疗效果。因此，针对多个靶点的双特异性抗体（bsAbs）应运而生。与单特异性的单克隆抗体相比， bsAbs是一类可以介导新的作用机制的抗体。2014年，首个靶向CD19/CD3ε的双特异性T细胞接合器（BiTE）blinatumomab被FDA批准用于治疗急性淋巴细胞白血病（ALL）。自那时起，bsAbs掀起了一阵开发热潮。截至2020年底，有三种bsAbs（catumaxomab、blinatumomab和emicizumab）获得批准。尤其最近几年，3年中新增了11种bsAbs获得了监管机构的批准，其中9种被批准用于治疗癌症(amivantamab, tebentafusp, mosunetuzumab, cadonilimab, teclistamab, glofitamab, epcoritamab, talquetamab, elranatamab) ，2种用于非肿瘤适应症(faricimab, ozoralizumab) 。值得注意的是，其中emicizumab和faricimab，已经取得了轰动性的地位，显示了这类新型疗法的前景。在接下来的关键十年，bsAb有望在血液系统恶性肿瘤、实体瘤和非肿瘤适应症中获得更多的批准，使bsAbs成为治疗药物的重要组成部分。-02-一、bsAb的模式抗体由四条多肽链组成，分子量较大的两条链称为重链(H链)，而分子量较小的两条链称为轻链(L链)。在单抗中，两条H链和两条L链的氨基酸组成完全相同，而双特异性抗体的开发是通过共表达两条不同的H链和两条不同的L链。从10种可能的H2L2重组混合物中获得功能性双特异性抗体是双特异性抗体开发的最初挑战之一，这通常称为链相关问题。 在过去几十年里，研究者们已经开发了许多策略，以解决这一问题。由这些策略诱导的不同设计特征或功能特性可用于所产生的双特异性抗体模式的分类。                基于片段的模式（Fragment-based formats） 基于片段的双特异性抗体简单地将多个抗体片段结合在一个分子中，不含Fc区域（fragment crystallizable，可结晶片段，与抗原结合片段Fab相对），避免了链相关问题，优势是产量高、成本低；缺点是半衰期相对较短。此外，基于片段的双特异性抗体可能会出现稳定性和聚合问题。 对称模式（Symmetric formats） 对称模式的双特异性抗体保留了Fc区域，更接近于天然抗体，但在大小和结构上有所不同。这些差异可能对与天然抗体相关的有利特性(如稳定性和溶解度)产生负面影响，从而可能损害这些双特异性抗体的理化和/或药代动力学特性。 不对称模式（Asymmetric formats） 大多数不对称模式的双特异性抗体与天然抗体非常相似，被认为具有最低免疫原性的潜力。不过，解决链相关问题可能涉及到的复杂工程可能会抵消一些不对称模式双特异性抗体的这一优势。-03- 二、bsAb的作用机制根据其功能机制，BsAb可分为4类：结合同一抗原的两个表位、细胞-细胞接合器、双功能调节剂和细胞治疗中的BsAb。其中，T细胞接合器是临床研究中应用最广泛的形式，已被证明能诱导肿瘤特异性免疫细胞激活。结合同一抗原的两个表位人们已经开发了同时针对同一靶抗原内2个不同表位的双副表位抗体。例如，靶向癌胚抗原（CEA）或VEGF2的bsAb被开发用于治疗癌症。人们还开发了几种bsAb来中和病毒抗原，例如，针对HBV表面抗原和HIV-1包膜蛋白的bsAb显示出针对同源抗原的中和活性。细胞接合器细胞接合器连接两种不同类型的细胞，主要是肿瘤细胞和T/NK细胞，以诱导肿瘤细胞溶解。细胞接合器由TAA靶向部分和效应细胞识别部分组成，并进一步分为T细胞接受器和NK细胞接受器。T细胞接合器利用TAA和TCR成分（主要是CD3），它们连接肿瘤细胞和T细胞，绕过TCR-MHC-I相互作用。因此，无论抗原特异性如何，T细胞结合器都会触发T细胞活化，产生包括穿孔素和颗粒酶在内的细胞毒性分子，以杀伤肿瘤细胞。BiTE是T细胞结合器的一种形式，通过靶向TAA和CD3的单链抗体将肿瘤细胞和T细胞结合，用于T细胞介导的肿瘤细胞杀伤。靶向CD19和CD3的blinatumomab是临床上典型的BiTE，2014年，blinatumomab成为第一个被FDA批准的BsAb，用于治疗ALL患者，在随后的几年里，blinatumomab的治疗范围进一步拓宽，2018年，FDA批准其用于首次或第二次完全缓解后MRD≥0.1%的pre-B ALL患者群体的治疗。目前，超过60例BiTE形式的双抗正在进行I/II期临床试验。NK细胞接合器将CD16A+NK细胞重定向至肿瘤细胞，诱导NK细胞活化。与BiTE相比，NK细胞接受者表现出较少的不良反应，如细胞因子释放综合征（CRS）和神经毒性。多种细胞毒性受体可激活NK细胞：CD16（FcγRIII）、天然细胞毒性受体（NCR；NKp30、NKp44、NKp46）、C型凝集素样受体NKG2D（CD314）和CD94/NKG2C。最近，抗CD30×CD16A的NK细胞接合器（AFM13）在AACR 2022的报告中展示了不俗的抗肿瘤效果。双功能调制剂双功能调节剂同时结合两种不同的免疫共刺激或共抑制分子，诱导靶细胞的功能改变。大多数双功能调节剂靶向PD-1/PD-L1轴和其他免疫抑制分子，如CTLA-4（CD152）、TIM-3、LAG-3或TIGIT。MEDI5752（PD-1×CTLA-4）抑制PD-1+激活的T细胞中CTLA-4的功能，诱导PD-1的快速内化和降解。与PD-1和CTLA-4单抗联合治疗相比，MEDI5752的活性显著增强。针对其他检查点分子的双功能性抑制剂，包括LAG-3和TIGIT，也正在开发中。过继细胞治疗中的bsAbs尽管CAR-T细胞疗法在血液系统恶性肿瘤中显示出疗效，但也观察到了副作用，包括CRS、神经毒性和靶向非肿瘤效应。为了将不良反应降至最低，正在进行用BsAbs体外激发T细胞的研究。与单独的BsAb和T细胞输注相比，在体外BsAb武装的T细胞治疗可诱导强烈的抗肿瘤反应，有效渗透到肿瘤部位，并减少细胞因子的释放，从而将系统不良反应降至最低。OKT3×hu3F8 BsAb武装T细胞（GD2BATs）在体外诱导特异性杀伤GD2阳性神经母细胞瘤和骨肉瘤细胞系。在GD2阳性肿瘤患者的I期试验中，GD2BATs在一些患者中显示出临床反应，且无明显副作用。-04-三、bsAb的未来展望在未来的十年里，预计还会批准更多具有改变医疗实践潜力的bsAbs。在肿瘤学中，靶向不同细胞表面受体的分化型双RTK信号抑制剂的开发仍然是一个活跃和先进的临床研究领域。例如靶向EGFR/LGR5的 petosemtamab、靶向HER2/HER3的zenocutuzumab以及靶向HER2双表位的zanidatamab，这几个正在美国进行审评中。这方面需要关注的另一个非常重要的领域是使用bsAbs产生的双特异性抗体偶联偶联物（bsADC），一些bsADC正在后期临床试验中进行研究，包括靶向HER2的zanidatamb zovodotin（ZW49）以及具有靶向c-MET双表位的REGN5093。开发用于治疗不同血液系统恶性肿瘤的TCE仍将是双抗治疗的主要研究领域，因为这类疗法已经证明了其临床益处。目前，基于不对称1 + 1 形式的odronextamab（CD20/CD3ε）80和 linvoseltamab（BCMA/CD3ε）正在接受审评，可能会在2024年获得批准、其它各种TCE正在NHL、多发性骨髓瘤和AML等适应症中进行后期临床开发。重要的是，新出现的数据也支持了TCE未来也可能在实体瘤中获得更的广泛应用。bsAb另一个主要研究领域仍然是开发双靶向免疫检查点抑制剂，例如PD-1和CTLA-4或LAG-3（tebotelimab）。这些双检查点抑制剂中的目前正在进行后期临床试验，结果将显示，与PD-1/PD-L1单克隆抗体与CTLA-4或LAG-3的联合用药相比，它们在疗效和安全性方面是否优越。值得注意的是，双靶向PD-1/VEGF抑制剂ivonescimab目前正在接受中国国家药品监督管理局的审评，用于治疗NSCLC。最后，鉴于bsAbs的多功能性和介导全新MOAs的潜力，bsAbs领域有望看到更多新兴的方法和候选药物进入临床，有望在未来几年提供肿瘤学和非肿瘤学适应症的关键数据，包括在感染/病毒学、自身免疫、代谢、神经病学和眼科的应用。这些新概念包括包括：1）不同于TCE的效应细胞接合器，例如髓系细胞、NK或γδ-T细胞， 2）前药概念，以肿瘤或肿瘤微环境特异性原位激活的bsAbs， 3）联合膜蛋白内化和降解的PROTAC样bsAb， 4）基于抗体的细胞因子模拟物，以触发细胞因子受体，以及 5）将bsAbs递送跨越屏障（如血脑屏障）的独特解决方案，其可用于治疗神经退行性疾病和其他疾病。参考资料：1.Development of Bispecific Antibody for CancerImmunotherapy: Focus on T Cell Engaging Antibody. Immune Netw. 2022 Feb; 22(1): e4.2. A pivotal decade for bispecific antibodies?. MAbs. 2024 Jan-Dec;16(1):2321635.公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。