CD16a

AFM24 combination with atezolizumab (AFM24-102): Follow-up of the Phase 1/2a combination study confirmed four responses in the non-small cell cancer (NSCLC) EGFR-wildtype cohort: one complete response (CR), three partial responses (PR), and seven stable disease patients in the 15 heavily pretreated patients who were evaluated. Mature progression free survival (PFS) data from the 15 EGFR-wildtype NSCLC patients and initial efficacy data from the EGFR-mutant NSCLC cohorts are expected in Q2 2024. Acimtamig (AFM13) combination with AlloNK® (AB-101) natural killer (NK) cells (LuminICE-203): Company on track to report initial efficacy and safety data in Q2 2024. AFM28: Currently enrolling patients in the sixth and final cohort of the Phase 1 dose-escalation study in patients with CD123-positive relapsed/refractory (r/r) AML. Restructuring completed: Company is focused on advancing its three clinical programs. Cash runway into H2 2025: As of December 31, 2023, cash, cash equivalents and investments were €72.0 million. MANNHEIM, Germany, March 28, 2024 (GLOBE NEWSWIRE) -- Affimed N.V. (Nasdaq: AFMD) (“Affimed” or the “Company”), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, today reported financial results and provided an update on clinical and corporate progress for the year ended December 31, 2023. “The clinical achievements in 2023 with our three programs, AFM24, acimtamig, and AFM28, provide a strong foundation for us to deliver on meaningful clinical milestones across the portfolio in 2024 and beyond,” said Dr. Andreas Harstrick, Chief Medical Officer and interim Chief Executive Officer at Affimed. “We have seen compelling responses in treatment refractory NSCLC EGFR-wt patients and will report mature PFS data of these patients as well as response data from the NSCLC EGFR-mut cohort in the second quarter. With the LuminICE-203 study of acimtamig with AlloNK successfully launched in 2023, we are progressing toward an initial data update in the second quarter. The long-term follow-up data for study for the AFM13-104, presented at ASH, demonstrating that approximately 30% of patients remain in remission beyond 1 year, have further enhanced our confidence in the therapeutic potential of acimtamig in combination with NK cells. Finally, AFM28 has reached the final dose level in the escalation study providing the basis for continued development. With all three clinical programs moving forward, we are focused on the execution of these programs confident in Affimed’s ability to fulfill our overarching mission of delivering innovative therapies to cancer patients.” Program Updates AFM24 (EGFR/CD16A tumors) As of January 4, clinical response update to the Phase 1/2a AFM24-102 trial in EGFR-wt NSCLC reported 4 confirmed responses, including 1 CR, 3 PRs, and 7 stable diseases in 15 heavily pre-treated patients, resulting in a disease control rate of 73 percent. All patients were pre-treated with platinum-based chemotherapy and checkpoint inhibitors PD [L]-1. Based on the promising results, Affimed expanded enrollment in this cohort to 40 patients. In addition, the company continues to enroll in the EGFR-mut NSCLC cohort for a planned number of 25 patients. Mature PFS data from the first 15 patients from the EGFR-wt cohort and response data from the EGFR-mut cohort are expected in Q2 2024. Acimtamig (AFM13; CD30/CD16A tumors) Initial safety and efficacy data from the LuminICE-203 (AFM13-203) study expected in Q2 2024. LuminICE-203 is a Phase 2 clinical study investigating acimtamig in combination with Artiva’s AlloNK cells in patients with r/r classical Hodgkin lymphoma (HL). Safety Review Committee meeting and initiation of enrollment in cohorts 3 and 4 is expected mid-April. Updated Phase 1/2 AFM13-104 study data demonstrated an ORR of 97% and a CR rate of 78% in 32 patients with r/r HL, presented at ASH 2023. As of the cutoff date, the median EFS was 9.8 months with 84% patients alive at 12 months. The median duration of response was 8.8 months. The treatment regimen continues to demonstrate a good safety and tolerability pro no cases of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GVHD) of any grade. The oral presentation included a total of 42 patients enrolled, with 36 patients treated at the recommended Phase 2 dose (RP2D). All patients were heavily pretreated and refractory to their most recent line of therapy with active progressive disease at the time of enrollment. AFM28 (CD123/CD16A) Completed enrollment of the fifth cohort, recruiting patients in the sixth and final cohort in the multi-center Phase 1 open-label, dose-escalation study (AFM28-101), of AFM28 monotherapy in CD123-positive r/r AML. No dose-limiting toxicities were reported. Further clinical development of AFM28 is planned in combination with an allogeneic off-the-shelf NK cell product. Corporate Restructuring: The corporate restructuring announced earlier this year has been fully implemented. The restructuring included a streamlining of operations resulting in a 50% reduction in the Company’s workforce. The Company is focusing resources on advancing its clinical programs, AFM24, acimtamig, and AFM28, through the various stages of development. Upcoming Milestones: Data from the NSCLC expansion cohorts in the Phase 1/2a AFM24+atezolizumab combination study expected in Q2 2024. Initial data readout from the LuminICE-203 (AFM13 combination with AlloNK NK cells) study expected in Q2 2024. Further progress updates from AFM28-101 dose escalation expected in Q2 2024. Full Year 2023 Financial Highlights Affimed’s consolidated financial statements are prepared in accordance with International Financial Reporting Standards (IFRS) as issued by the International Accounting Standard Board (IASB). The consolidated financial statements are presented in Euros (€), the Company’s functional and presentation currency. As of December 31, 2023, cash, cash equivalents and investments totaled €72.0 million compared to €190.3 million on December 31, 2022. Based on our current operating plan and assumptions, we anticipate that our liquidity will support operations into H2 2025. Net cash used in operating activities for the year ended December 31, 2023, was €110.3 million compared to €104.9 million for the year ended December 31, 2022. Total revenue for the year ended December 31, 2023, was €8.3 million compared with €41.4 million for the year ended December 31, 2022. Revenue in 2022 and 2023 predominantly relates to the Roivant and Genentech collaborations for which we have now completed the work assigned to us under the respective collaboration agreements. Research and development expenses for the year ended December 31, 2023, were €95.0 million compared to €98.8 million in 2022. General and administrative expenses for the year ended December 31, 2023, were €24.7 million compared to €32.1 million for the year ended December 31, 2022. The decrease was due to a decline in legal, consulting and insurance expenses, as well as share-based payment expenses. Net finance income/costs for the year ended December 31, 2023, were €0.7 million compared to €2.1 million for the year ended December 31, 2022. Net finance income/costs are largely due to foreign exchange gains/losses related to assets denominated in U.S. dollars as a result of currency fluctuations between the U.S. dollar and Euro during the year. The weighted number of common shares outstanding for the year ended December 31, 2023, was 14.9 million, adjusted to reflect the impact of the reverse stock split executed in the first quarter of 2024. Net loss for the year ended December 31, 2023, was €105.9 million, or €7.09 loss per common share compared with a net loss of €86.0 million, or €6.04 loss per common share, for the year ended December 31, 2022. Additional information regarding these results is included in the notes to the consolidated financial statements as of December 31, 2023, included in Affimed’s filings with the U.S. Securities and Exchange Commission (SEC). Note on International Financial Reporting Standards (IFRS) Affimed prepares and reports consolidated financial statements and financial information in accordance with IFRS as issued by the IASB. None of the financial statements were prepared in accordance with U.S. Generally Accepted Accounting Principles. Affimed maintains its books and records in Euro. Conference Call and Webcast Information Affimed will host a conference call and webcast on March 28, 2024, at 8:30 a.m. EDT / 13:30 CET to discuss full year 2023 financial results and corporate developments. The conference call will be available via phone and webcast. The live audio webcast of the call will be available in the “Webcasts” section on the “Investors” page of the Affimed website at . To access the call by phone, please use link: , and you will be provided with dial-in details and a pin number. Note: To avoid delays, we encourage participants to dial into the conference call 15 minutes ahead of the scheduled start time. A replay of the webcast will be accessible at the same link for 30 days following the call. About Affimed N.V. Affimed (Nasdaq: AFMD) is a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer by actualizing the untapped potential of the innate immune system. The Company’s innate cell engagers (ICE®) enable a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors. ICE® are generated on the Company’s proprietary ROCK® platform which predictably generates customized molecules that leverage the power of innate immune cells to destroy tumor cells. A number of ICE® molecules are in clinical development, being studied as mono- or combination therapy. Headquartered in Mannheim, Germany, Affimed is led by an experienced team of biotechnology and pharmaceutical leaders united by a bold vision to stop cancer from ever derailing patients’ lives. For more about the Company’s people, pipeline and partners, please visit: . Forward-Looking Statement This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. Forward-looking statements appear in a number of places throughout this release and include statements regarding the Company’s intentions, beliefs, projections, outlook, analyses and current expectations concerning, among other things, the potential of acimtamig (AFM13), AFM24, AFM28 and the Company’s other product candidates, the value of its ROCK® platform, its ongoing and planned preclinical development and clinical trials, its corporate restructuring, the associated headcount reduction and the impact this may have on Company’s anticipated savings and total costs and expenses, its collaborations and development of its products in combination with other therapies, the timing of and its ability to make regulatory filings and obtain and maintain regulatory approvals for its product candidates, its intellectual property position, its collaboration activities, its ability to develop commercial functions, clinical trial data, its results of operations, cash needs, financial condition, liquidity, prospects, future transactions, growth and strategies, the industry in which it operates, the macroeconomic trends that may affect the industry or the Company, such as the instability in the banking sector experienced in the first quarter of 2023, impacts of the COVID-19 pandemic, the benefits to Affimed of orphan drug designation, the impact on its business by political events, war, terrorism, business interruptions and other geopolitical events and uncertainties, such as the Russia-Ukraine conflict, the fact that the current clinical data of acimtamig in combination with NK cell therapy is based on acimtamig precomplexed with fresh allogeneic cord blood-derived NK cells from The University of Texas MD Anderson Cancer Center, as opposed to Artiva’s Allo-NK NK cells and other uncertainties and factors described under the heading “Risk Factors” in Affimed’s filings with the SEC. Given these risks, uncertainties, and other factors, you should not place undue reliance on these forward-looking statements, and the Company assumes no obligation to update these forward-looking statements, even if new information becomes available in the future. Investor Relations Contact Alexander Fudukidis Director, Investor Relations E-Mail: a.fudukidis@affimed.com Tel.: +1 (917) 436-8102 Affimed N.V. Consolidated statements of comprehensive loss (in € thousand) 2023 2022 2021 Revenue 8,275 41,353 40,366 Other income and expenses – net 4,697 1,417 1,310 Research and development expenses (94,958 ) (98,814 ) (81,488 ) General and administrative expenses (24,675 ) (32,075 ) (24,218 ) Operating loss (106,661 ) (88,119 ) (64,030 ) Finance income / (costs) – net 726 2,117 6,509 Loss before tax (105,935 ) (86,002 ) (57,521 ) Income taxes (3 ) (2 ) (2 ) Loss for the period (105,938 ) (86,004 ) (57,523 ) Other comprehensive loss Items that will not be reclassified to profit or loss Equity investments at fair value OCI – net change in fair value 0 (6,047 ) (7,693 ) Other comprehensive loss 0 (6,047 ) (7,693 ) Total comprehensive loss (105,938 ) (92,051 ) (65,216 ) Basic and diluted loss per share in € per share (undiluted = diluted) (7.09 ) (6.04 ) (4.81 ) Weighted number of common shares outstanding 14,939,916 14,236,229 11,950,238 Affimed N.V. Consolidated statements of financial position (in € thousand) December 31, 2023 December 31, 2022 ASSETS Non-current assets Intangible assets 25 58 Leasehold improvements and equipment 4,905 3,823 Right-of-use assets 8,039 561 12,969 4,442 Current assets Cash and cash equivalents 38,529 190,286 Investments 33,518 0 Other financial assets 851 0 Trade and other receivables 5,327 2,697 Inventories 463 628 Other assets and prepaid expenses 5,500 2,459 84,188 196,070 TOTAL ASSETS 97,157 200,512 EQUITY AND LIABILITIES Equity Issued capital 1,500 1,493 Capital reserves 593,666 582,843 Fair value reserves (1,231) (1,231) Accumulated deficit (536,128) (430,190) Total equity 57,807 152,915 Non current liabilities Borrowings 6,319 11,687 Contract liabilities 464 1,083 Lease liabilities 6,660 176 Total non-current liabilities 13,443 12,946 Current liabilities Trade and other payables 18,916 19,077 Borrowings 5,833 5,930 Lease liabilities 539 396 Contract liabilities 619 9,248 Total current liabilities 25,907 34,651 TOTAL EQUITY AND LIABILITIES 97,157 200,512 Affimed N.V. Consolidated statements of cash flows (in € thousand) 2023 2022 2021 Cash flow from operating activities Loss for the period (105,938) (86,004) (57,523) Adjustments for the period: - Income taxes 3 2 2 - Depreciation and amortization 1,749 2,899 1,334 - Net gain from disposal of subsidiary (4,339) 0 0 - Net loss on disposal of leasehold improvements and equipment 82 0 0 - Share-based payments 10,714 19,110 11,820 - Finance income / (costs) – net (726) (2,117) (6,509) (98,455) (66,110) (50,876) Change in trade and other receivables 1,093 2,113 (2,369) Change in financial assets (851) 0 0 Change in inventories 100 (207) (175) Change in other assets and prepaid expenses (2,737) 1,075 (2,274) Change in trade, other payables, provisions and contract liabilities (9,766) (41,048) (29,990) (110,616) (104,177) (85,684) Interest received 1,743 564 0 Paid interest (1,393) (1,277) (905) Paid income tax (3) (2) (2) Net cash used in operating activities (110,269) (104,892) (86,591) Cash flow from investing activities Purchase of intangible assets 0 (37) (1,654) Purchase of leasehold improvements and equipment, including upfront payments for right-of-use assets (3,729) (659) (2,196) Cash received from the sale of financial assets 938 6,301 0 Cash paid for investments in financial assets (34,246) 0 0 Cash received from sale of subsidiary 978 0 0 Net cash (used)/generated in investing activities (36,059) 5,605 (3,850) Cash flow from financing activities Proceeds from issue of common shares, including exercise of share-based payment awards 235 95,907 124,460 Transaction costs related to issue of common shares (35) (6,037) (7,412) Proceeds from borrowings 0 0 17,500 Transaction costs related to borrowings 0 0 (311) Repayment of lease liabilities (491) (733) (564) Repayment of borrowings (5,929) (580) (92) Net cash (used)/generated in financing activities (6,220) 88,557 133,581 Exchange rate related changes of cash and cash equivalents 791 3,386 7,636 Net changes to cash and cash equivalents (152,548) (10,730) 43,140 Cash and cash equivalents at the beginning of the period 190,286 197,630 146,854 Cash and cash equivalents at the end of the period 38,529 190,286 197,630 Affimed N.V. Consolidated statements of changes in equity (in € thousand) Issued Capital Fair Value Accumulated Total capital reserves reserves deficit equity Balance as of January 1, 2021 983 345,164 1,720 (275,874) 71,993 Issue of common shares 240 114,197 114,437 Exercise of share-based payment awards 11 2,906 2,917 Equity-settled share-based payment awards 11,820 11,820 Loss for the period (57,523) (57,523) Other comprehensive loss (7,693) (7,693) Balance as of December 31, 2021 1,234 474,087 (5,973) (333,397) 135,951 Balance as of January 1, 2022 1,234 474,087 (5,973) (333,397) 135,951 Issue of common shares 259 89,545 89,804 Exercise of share-based payment awards 0 101 101 Equity-settled share-based payment awards 19,110 19,110 Transfer of cumulative loss on sale of financial assets 10,789 (10,789) 0 Loss for the period (86,004) (86,004) Other comprehensive loss (6,047) (6,047) Balance as of December 31, 2022 1,493 582,843 (1,231) (430,190) 152,915 Balance as of January 1, 2023 1,493 582,843 (1,231) (430,190) 152,915 Issue of common shares 7 109 116 Equity-settled share-based payment awards 10,714 10,714 Loss for the period (105,938) (105,938) Balance as of December 31, 2023 1,500 593,666 (1,231) (536,128) 57,807

点击上方的 行舟Drug ▲ 添加关注前言迄今为止，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，它的发展改变了肿瘤免疫治疗的领域。目前，人们正在研究越来越多的针对癌症治疗的不同类型的bsAbs。这些类型包括双靶向抑制剂，其作用于不同水平的肿瘤增殖、血管形成和转移；以及双特异性抗体偶联药物、T细胞结合器、双特异性自然杀伤细胞接合器（NKCE）和先天免疫细胞接合器。其他类型还包括双特异性免疫检查点抑制剂（CPI）、共刺激bsAbs和融合蛋白、具有联合检查点抑制和共刺激特征的bsAbs、在肿瘤微环境（TME）中特异性激活的bsAb，以及将过继T细胞治疗和治疗性抗体相结合的新方法。目前，有300多项临床试验涉及200多种不同的双特异性抗体分子，其中约75%用于治疗实体瘤，25%用于治疗血液系统恶性肿瘤。有10种bsAb药物已被批准用于癌症治疗，其中9种在美国和/或欧洲获得批准，cadonilimab在中国获得批准。到目前为止，临床中开发的很大一部分bsAbs已经处于后期阶段（II期和III期）。另外，可以发现，治疗实体瘤的bsAbs主要由免疫调节剂主导，包括双CPI（约45%）和TCE（约33%），其次是靶向双途径、ICEs和ADC的bsAb。bsAb的发展史BsAbs最初的概念是由AlfredNisonof在20世纪60年代首次提出的。他将两个不同的抗原结合位点结合在一个分子中，并从抗牛γ球蛋白和抗卵清蛋白单价片段的混合物中获得了一个具有双重特异性的F(ab’)2分子。1975年，Köhler和Milstein发明了杂交瘤技术，最终解决了生产单克隆抗体的问题，开启了单克隆抗体治疗的新时代。1983年，Milstein和Cuello开创了quadroma技术，该技术基于分泌Abs混合物的两种不同杂交瘤细胞系的体细胞融合，包括具有双重特异性的鼠IgG形式的bsAb。然而，bsAb的低产率以及难以从密切相关的错配副产物中纯化所需的Ab是一个重大问题。1988年，James Huston和他的同事发明了单链抗体片段（scFv），它最大限度地减少了复性问题，例如不正确的结构域配对或聚集。1996年，Genentech的科学家们利用重组DNA技术发明了knob-into-hole技术，克服了Quadrome技术的局限性。通过在人类IgG的CH3结构域之间的界面突变选定的氨基酸，可以减少IgG重链的错配。这种技术利用更有利的蛋白质相互作用，最终可以形成高达90%的正确双特异性重链配对。随后，随着抗体工程和生物学的进展，bsAb的不同概念和结构正在不断演变。靶向双受体抑制的bsAb许多参与细胞信号传导的细胞表面蛋白，如RTK和相关受体，是基于抗体治疗的有效靶点。尽管靶向一个确定的信号受体的抗体治疗是非常有效的，但疾病相关表型通常由不止一种途径触发。这种冗余允许细胞通过使用其他补偿信号通路，从而耐受药物的生长抑制或细胞毒性诱导。同时调节不同疾病相关信号受体或通路的bsAbs可以减少或克服这一限制。Amivantamab（JNJ-61186372）靶向EGFR和肝细胞生长因子受体（MET），两种受体都能触发非小细胞肺癌（NSCLC）的增殖。因此，阻断两种受体比仅阻断一种途径能够更有效地抑制NSCLC的生长。Amivantamab已被FDA批准用于治疗携带EGFR外显子20插入突变的NSCLC亚型。一项随机III期研究的数据显示，在这部分患者中，与单独化疗相比，Amivantamab联合化疗具有显著优越性。另外一些针对肿瘤不同第二靶点的EGFR的bsAbs也正在临床开发中。例如，petosemtamab（MCLA-158）靶向EGFR和LGR5，LGR5是一种癌症干细胞相关的细胞表面受体。Petosemtamab目前正在包括晚期头颈部鳞状细胞癌在内的实体瘤患者的I/II期试验中进行评估（NCT03526835）。靶向配体受体抑制的bsAbbsAbs可以同时阻断两种不同的配体，或者是配体和受体的组合。VEGF和血管生成素2（ANG2）的双重靶向作用分别阻断VEGFR和血管生成因子1受体（TIE2）的激活，这两种途径涉及血管生成。vanucizumab，一种靶向VEGFA和ANG2的bsAb，在临床前模型中与化疗联合显示出抗肿瘤、抗血管生成和抗转移作用。BI836880是一种三特异性纳米抗体融合蛋白，由三个靶向VEGFA、ANG2和HSA的纳米抗体组成，后者可延长其血清半衰期。目前正在头颈部鳞状细胞癌、NSCLC和其他实体瘤患者的I期研究中进行评估。此外，靶向VEGF可以进一步设计成联合靶向肿瘤细胞上的PD-L1或T细胞上的PD-1，从而将抗血管生成与肿瘤免疫学方法联系起来。例如靶向PD1和VEGF的ivonescimab（AK112），其目前已在中国获批用于。其他bsAbs靶向PDL1和VEGF，包括PM8002，该药物正在NSCLC患者的II/III期研究（NCT05756972）中进行评估。靶向受体激活的bsAb许多抗肿瘤反应是通过激活细胞表面受体介导的，包括通过诱导细胞凋亡的免疫反应或细胞死亡。其中一种方法是靶向递送受体激活配体，如生长因子、细胞因子和（共）免疫刺激配体，将其融合到抗体或抗体片段中，以诱导局部或组织特异性激动活性，从而诱导细胞反应。越来越多的这种抗体-配体融合蛋白正在进入临床试验。受体激活也可以使用激动性抗体来实现。针对靶抗原和肿瘤坏死因子超家族（TNFRSF）成员的bsAbs已被证明是具有强大活性和肿瘤选择性的激动分子。RG7386（RO6874813）是一种四价bsAb，靶向癌症相关成纤维细胞上的FAPα和DR5，在具有FAPα间质表达的小鼠模型中具有效和选择性的肿瘤细胞杀伤，并已进入临床测试。此外，BI905711，一种靶向DR5和CDH17的四价双特异性IgG-scFv融合蛋白，目前处于I期临床研究中。靶向递送有效载荷的bsAb存在两种概念上不同的方法来利用bsAbs靶向递送有效载荷，如细胞毒性药物或放射性药物。第一种方法，预靶向治疗，使用bsAb的一个臂特异性靶向肿瘤细胞，另一个臂随后捕获有效载荷到肿瘤细胞。GD2 x DOTA是一种识别GD2的bsAb，并捕获放射性有效载荷177Lu-DOTA，其在TME中组装。在没有四聚化的情况下，由于半衰期，它会被迅速从外围清除。然而，到目前为止，临床试验中很少有bsAbs利用这种MoA，这可能是因为放射性预靶向涉及复杂的导流，限制了其普遍适用性。第二种方法通过递送偶联到双特异性抗体上的细胞毒性有效载荷，实现肿瘤细胞的特异性靶向。目前，bsADC已成为肿瘤药物开发的热点，已有多款bsADC进入临床开发，如ZW49、REGN5093、BL-B01D1等。靶向癌症免疫治疗的bsAb癌症免疫疗法中使用的大多数bsAbs通过T细胞驱动的天然或内源性免疫发挥作用，包括免疫检查点抑制（CPIs）效应细胞接合器（包括TCE和ICEs）以及共刺激性bsAb。双免疫检查点抑制许多抑制免疫检查点的单特异性抗体，如CTLA4或PD-1/PDL-1，已被批准用于癌症免疫疗法。将检查点抑制性抗体疗法扩展到bsAbs可以减少不期望的副作用，并增强疗效。大多数双免疫检查点抑制剂靶向PD-1/PD-L1轴和其他免疫抑制分子，如CTLA-4、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。效应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。共刺激bsAbs高效、持久和局部受限的抗肿瘤免疫反应需要共刺激和共抑制信号来严格调节细胞毒性T细胞、自然杀伤细胞和巨噬细胞的激活、分化和维持。TNFRSF家族的成员（如4-1BB、CD40、OX40、GITR、CD27或CD30）以及CD28免疫球蛋白超家族（如CD28、CTLA4、PD-1、ICOS、BTLA)及其相应的配体在介导免疫调节信号中发挥着重要作用。靶向这些免疫调节途径可以增强免疫治疗。PRS-343（cinrebafusp），是一种针对HER2和4-1BB的四价bsAb，在IND研究中其耐受性良好，没有明显和相关的药物相关毒性；在接受有效剂量治疗的患者中（n=33），12%的患者达到ORR，包括1个CR，疾病控制率（DCR）为52%。bsAbs中通过4-1BB进行肿瘤选择性共刺激的其他靶点还包括EGFR、PSMA、CLDN18.2、B7H4、CEACAM5、HER2、PD-L1和FAP。此外，十多种针对PD-L1和4-1BB的不同bsAbs处于I期或II期试验中。bsAb的新概念bsAbs的领域仍在进一步探索和扩展技术和应用，可能提供目前正在开发的bsAb尚未解决的治疗概念。三特异性TCE共刺激信号可以与双特异性TCE组合以促进更加有效的T细胞活化。这样的三特异性TCE目前正在针对TAA和CD3的临床试验中，并且进一步包含抗CD28结合位点。SAR443216是一种针对HER2×CD3×CD28的三特异性抗体，能够强力激活CD4+和CD8+T细胞，诱导T细胞增殖、细胞因子和颗粒酶B的释放，以及T细胞介导的对表达HER2的肿瘤细胞的杀伤，其目前处于I期临床研究中。在类似的方法中，SAR442257是另一种CD38×CD3×CD28的三特异性抗体。前药方法一种新兴的方法是在肿瘤处选择性激活的前药，产生具有高度肿瘤特异性功能的bsAbs。前药转化为功能性bsAbs可以通过环境触发因素如肿瘤相关蛋白酶来实现。双重肿瘤靶向的另一种前药方法依赖于来自两个具有分裂CD3ε结合部分的肿瘤特异性组装。这些分子需要被设计为非活性的独立实体并在循环中，使得它们仅在肿瘤抗原结合和随后的原位组装时被激活。PROTAC bsAbs另一个新兴概念和新的MoA利用bsAbs通过靶向降解来抑制增殖相关过程。类似于双特异性或多特异性小分子蛋白水解靶向嵌合体（PROTACs），bsAbs可被设计为触发参与癌症发展或进展的表面蛋白的内化和随后的降解。这样的bsAbs同时与靶向降解的蛋白质和降解的因子结合，并触发内化，如膜上的E3泛素连接酶或转铁蛋白受体。目前，抗体-PROTAC概念仍处于早期开发阶段，迄今为止还没有进入临床研究。bsAb递送bsAb开发中另一个重要的新兴概念是bsAb的局部产生和随后的局部递送，如通过脂质纳米颗粒介导的mRNA递送的CLDN6 TCE、溶瘤病毒或包括CAR-T细胞在内的基因治疗方法。细胞因子模拟抗体最后，bsAbs也可以作为细胞因子模拟物或所谓的合成细胞因子激动剂。scFvs或基于单域抗体VHH的方法可以通过模拟IL-2或IL-15、IL-18、I型干扰素和IL-10来有效地触发细胞因子信号传导。这种基于抗体的细胞因子模拟物可能在癌症免疫疗法中具有各种应用。小结bsAbs领域最近取得了实质性进展，到2023年底，已有十几种bsAbs获得批准，许多不同的方法正在临床上进行测试。尽管如此，由于癌症的异质性和适应性，这些方法中的任何一种都不太可能成为普遍的癌症免疫疗法。相反，抗体需要针对某些应用量身定制，并将依赖于与其他方法的结合，以最大限度地提高其疗效和安全性。在不久的将来，多特异性抗体疗法的发展可能会在以下四个领域出现增长：针对具有明确依赖性的肿瘤相关RTK的bsAbs；用于以增加的选择性靶向肿瘤的bsADC；用于靶向降解适用于各种途径的细胞表面蛋白的双特异性PROTAC；以及用于癌症免疫疗法的多特异性抗体。与其他治疗癌症的药物一样，通过改进的诊断方法和新的开发模式，将bsAbs和多特异性抗体疗法应用于早期患者，对于实现治愈癌症患者的目标至关重要。参考文献：1. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov.2024 Mar 6.2. Development of Bispecific Antibody for CancerImmunotherapy: Focus on T Cell Engaging Antibody. Immune Netw. 2022 Feb; 22(1): e4.文章信息源于公众号小药说药，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新 欢迎订阅+医药大数据|行业动态|政策解读

中国南京和特拉华州纽瓦克 2024年3月21日 /美通社/ -- 博奥信（以下简称："公司"），一家处于临床阶段的全球化创新生物技术公司，今天宣布将在4月5日至10日举办的美国癌症研究协会年会（AACR）上展示公司三项临床前创新管线研究数据，包括BSI-111（抗CD16a单克隆抗体）、BSI-730（HER2/PD-L1双特异性抗体ADC）、BSI-093（抗BTN3A单克隆抗体）。 "我们很高兴能在AACR上展示博奥信最新的研究成果。BSI-093、BSI-111和BSI-730在临床前研究中展现出良好的生物学活性与功能，可以支持各项临床前研究工作持续推进。"博奥信创始人、董事长兼首席执行官陈明久博士表示。"我们期待在AACR年会期间与业内同行交流沟通博奥信药物管线的最新数据。" 一、壁报详细内容： 标题： BSI-111，一种用于构建NK细胞衔接器平台的具有强效激动剂活性的高选择性抗CD16a单克隆抗体 BSI-111是一种全人源单克隆抗体，由博奥信H³抗体发现平台开发获得。BSI-111可特异性结合CD16a而不识别CD16b，并能够以高亲和力结合CD16A的两种等位基因变体(158V或158F)。BSI-111其具有良好的生物学活性功能，是开发下一代基于CD16a的NK细胞衔接器关键组成。 时间：2024年4月8日上午9:00-下午12:30 地点：壁报第2区26号 摘要编号：1343 标题： BSI-730，一种用于开发同类首创双特异性ADC药物的抗HER2xPD-L1双特异性抗体 BSI-730是一种靶向HER2和PD-L1的新型双特异性抗体分子，由博奥信SynTracer® 高通量抗体内吞筛选平台开发获得，可以用于开发同类首创的双特异性ADC。与曲妥珠单抗相比，BSI-730显示出与HER2相当的结合活性和内吞活性。BSI-730在PD-L1结合、内吞活性，以及在PD-1/PD-L1阻断方面等方面都显示与亲本抗PD-L1抗体相当的生物活性。 时间：2024年4月8日下午1:30-5:00 地点：壁报第21区16号 摘要编号：3135 标题： BSI-093，一种用于激活Vγ9Vδ2 T细胞肿瘤免疫治疗的同类最优抗BTN3A单克隆抗体 BSI-093是一种人源化抗BTN3A激动性单克隆抗体，具有强的Vγ9Vδ2 T细胞活化活性。BTN3A家族包括BTN3A1、BTN3A2和BTN3A3，是Ig超家族受体的成员，对激活Vγ9Vδ2T细胞介导的抗肿瘤免疫反应至关重要。与正常组织对照相比，BTN3A在胆管癌、食道癌、头颈部鳞状细胞癌的肿瘤样本中的表达显著更高。 时间：2024年4月9日下午1:30-5:00 地点：壁报第3区7号 摘要编号：5298 此外，博奥信的合作伙伴正大天晴、OBI Pharma和Pyxis Oncology也将在AACR上展示最新研究成果。 二、合作伙伴壁报详细内容： 1. 合作伙伴：正大天晴 标题：CD40激动剂—TQB2916在晚期恶性肿瘤受试者中的I期临床研究 时间：2024年4月9日上午9:00-下午12:30 地点：壁报第48区20号 摘要编号：CT192 TQB2916（BSI-038）是一种人源化激动型抗 CD40单克隆抗体，与罗氏的selicrelumab相比，其结合亲和力高7倍，细胞生物活性高4倍。BSI-038通过与CD40受体结合触发抗原提呈细胞的增殖和活化。2019年7月，博奥信与正大天晴签署合作开发协议，正大天晴获得BSI-038的大中华区产品开发和商业化权益，博奥信则保留大中华区以外的产品开发和商业化权利。正大天晴正在国内开展一项针对晚期肿瘤的一期临床试验。 2. 合作伙伴： OBI Pharma （1）标题：OBI-992，一种新型抗TROP2 ADC，在动物模型中显示出优异的抗肿瘤效果 时间：2024年4月8日上午9:00-下午12:30 地点：壁报第23区4号 摘要编号：1893 （2）标题：新型抗TROP2 ADC OBI -992的特性分析研究 时间：2024年4月8日下午1:30-5:00 地点：壁报第21区11号 摘要编号：3130 （3）标题：OBI-992，一种具有优秀PK/PD特性和安全性的新型抗TROP2 ADC 时间：2024年4月10日上午9:00-下午12:30 地点：壁报第24区20号 摘要编号：7179 OBI-992（BSI-992）是由博奥信专有的SynTracer®高通量抗体内吞筛选平台开发出的一种人源化抗TROP2单克隆抗体。TROP2在多种癌细胞中高度表达，如胰腺、胃、肺、结直肠癌细胞，其过表达与实体肿瘤患者生存期较短相关。2021年12月，博奥信将BSI-992在大中华区以外的产品开发和商业化权益授权给OBI Pharma，博奥信保留大中华区的产品开发和商业化权益。OBI Pharma正在欧美开展针对多种实体瘤的临床I期试验。 3. 合作伙伴： Pyxis Oncology 标题：免疫检查点分子 Siglec-15 和 PD-L1 的基因表达相关性因癌症适应症而具有较大差异 时间：2024年4月8日上午9:00-下午12:30 地点：壁报第3区24号 摘要编号：1373 BSI-060T是一种全人源的抗Siglec-15单克隆抗体，其亲和力高10倍，基于PBMC的细胞生物活性, 以及药物半衰期等在多个关键技术指标上均显著超越对标抗体药物。Siglec-15是一种免疫抑制检查点，是促进肿瘤免疫正常化的潜在靶点，其在包括非小细胞肺癌、头颈部癌、甲状腺癌等多种实体肿瘤中显著上调。2022年3月，博奥信将BSI-060T在大中华区以外的产品开发和商业化权益授权给Pyxis Oncology，博奥信保留大中华区所有产品开发和商业化权益。Pyxis Oncology正在欧美进行针对多种实体瘤的一期临床试验。博奥信在中国获得临床批件。 关于博奥信 博奥信是一家处于临床阶段的全球化创新生物技术公司，致力于应用其专有的抗体技术平台开发创新疗法，使患者在免疫及肿瘤疾病的治疗中获益。成立于2017年，博奥信通过内部专有的H³（高通量，高含量，高效率）抗体发现平台、SynTracer® 高通量抗体内吞筛选平台、Flexibody® 双功能抗体技术平台及全球合作建立了一系列创新药物管线。自研产品Bosakitug（BSI-045B\/TQC2731，抗TSLP单抗）正在中美开展针对严重哮喘、慢性鼻窦炎伴鼻息肉和特应性皮炎的临床II期试验，另有7项自研合作产品在中美开展临床I期或II期试验。更多公司及管线信息，请访问 www.biosion.com。 联系人： Mason Xu mason.xu@biosion.com