Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy

Tiancheng Zhang, Youpei Lin, Qiang Gao, Tiancheng Zhang, Youpei Lin, Qiang Gao

Abstract

Advances in antibody engineering have led to the generation of more innovative antibody drugs, such as bispecific antibodies (bsAbs). Following the success associated with blinatumomab, bsAbs have attracted enormous interest in the field of cancer immunotherapy. By specifically targeting two different antigens, bsAbs reduce the distance between tumor and immune cells, thereby enhancing tumor killing directly. There are several mechanisms of action upon which bsAbs have been exploited. Accumulating experience on checkpoint-based therapy has promoted the clinical transformation of bsAbs targeting immunomodulatory checkpoints. Cadonilimab (PD-1 × CTLA-4) is the first approved bsAb targeting dual inhibitory checkpoints, which confirms the feasibility of bsAbs in immunotherapy. In this review we analyzed the mechanisms by which bsAbs targeting immunomodulatory checkpoints and their emerging applications in cancer immunotherapy.

Keywords: Antibody–drug conjugate; bispecific antibody; clinical trials; immunotherapy; tumor microenvironment.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Copyright © 2023 Cancer Biology & Medicine.

Figures

Figure 1
Figure 1
The immunoglobulin G (IgG) structure and schematic diagram of several representative bsAbs. The IgG is roughly “Y-shaped”. The two heavy chains are shown in blue and the two light chains are shown in green (A). IgG-like bsAbs (B). Non-IgG-like bsAbs (C). BiTE, bispecific T-cell engager; DART, dual-affinity retargeting molecule; DVD-Ig, dual-variable-domain immunoglobulin; scFv, single-chain variable fragment; TandAb, tandem diabody.
Figure 2
Figure 2
The bsAbs targeting immunomodulatory checkpoints. The checkpoint-targeted bsAbs are mainly divided into three categories: targeting dual inhibitory checkpoints (①); targeting co-stimulatory and inhibitory checkpoints (②); and targeting immunomodulatory checkpoints and non-checkpoint targets (③④). TAA, tumor-associated antigen; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor-β.

References

    1. Kaplon H, Chenoweth A, Crescioli S, Reichert JM. Antibodies to watch in 2022. MAbs. 2022;14:2014296.
    1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.
    1. Petroni G, Buque A, Coussens LM, Galluzzi L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Discov. 2022;21:440–62.
    1. Nisonoff A, Wissler FC, Lipman LN. Properties of the major component of a peptic digest of rabbit antibody. Science. 1960;132:1770–1.
    1. Fudenberg HH, Drews G, Nisonoff A. Serologic demonstration of dual specificity of rabbit bivalent hybrid antibody. J Exp Med. 1964;119:151–66.
    1. Parsons S, Murawa P, Koralewski P, Kutarska E, Kolesnik O, Stroehlein M, et al. Intraperitoneal treatment of malignant ascites due to epithelial tumors with catumaxomab: a phase II/III study. J Clin Oncol. 2008;26:3000–3000.
    1. Przepiorka D, Ko C-W, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu H-J, et al. Fda approval: blinatumomab. Clin Cancer Res. 2015;21:4035–9.
    1. Labrijn AF, Janmaat ML, Reichert JM, Parren P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
    1. Kong X. In: Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy. Xu J, editor. Singapore: Springer Singapore; 2020. Discovery of new immune checkpoints: family grows up; pp. 61–82.
    1. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49.
    1. Chiu ML, Gilliland GL. Engineering antibody therapeutics. Curr Opin Struct Biol. 2016;38:163–73.
    1. Milstein C, Cuello AC. Hybrid hybridomas and their use in immunohistochemistry. Nature. 1983;305:537–40.
    1. Lindhofer H, Mocikat R, Steipe B, Thierfelder S. Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies. J Immunol. 1995;155:219–25.
    1. Li H, Er Saw P, Song E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell Mol Immunol. 2020;17:451–61.
    1. Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, et al. Bispecific antibodies: from research to clinical application. Front Immunol. 2021;12:626616.
    1. Birch JR, Racher AJ. Antibody production. Adv Drug Deliv Rev. 2006;58:671–85.
    1. Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. Bites: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today. 2005;10:1237–44.
    1. Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, et al. Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol. 2010;399:436–49.
    1. Kipriyanov SM, Moldenhauer G, Schuhmacher J, Cochlovius B, Von der Lieth CW, Matys ER, et al. Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J Mol Biol. 1999;293:41–56.
    1. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.
    1. Sanmamed MF, Berraondo P, Rodriguez-Ruiz ME, Melero I. Charting roadmaps towards novel and safe synergistic immunotherapy combinations. Nat Cancer. 2022;3:665–80.
    1. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–68.
    1. Natoli M, Hatje K, Gulati P, Junker F, Herzig P, Jiang Z, et al. Deciphering molecular and cellular ex vivo responses to bispecific antibodies PD1-TIM3 and PD1-LAG3 in human tumors. J Immunother Cancer. 2022;10:e005548.
    1. Reader CS, Liao W, Potter-Landau BJ, Veyssier CS, Rhoades MC, Seal CJ, et al. Abstract 2874: The tetravalent structure of FS118, a bispecific antibody targeting LAG-3 and PD-L1, is required for its novel mechanism of LAG-3 shedding. Cancer Res. 2022;82:2874–2874.
    1. Wang J, Lou H, Cai H-B, Huang X, Li G, Wang L, et al. A study of AK104 (an anti-PD1 and anti-CTLA4 bispecific antibody) combined with standard therapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer (R/M CC) J Clin Oncol. 2022;40:106–106.
    1. Xing B, Da X, Zhang Y, Ma Y. A phase II study combining KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) and lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): updated efficacy and safety results. J Clin Oncol. 2022;40:4115–4115.
    1. Bonati L, Tang L. Cytokine engineering for targeted cancer immunotherapy. Curr Opin Chem Biol. 2021;62:43–52.
    1. Garber K. Immune agonist antibodies face critical test. Nat Rev Drug Discov. 2020;19:3–5.
    1. Garralda E, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso P, et al. 412 first-in-human phase I/a trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors. J Immunother Cancer. 2020;8:A250–1.
    1. Jiang W, Fang L, Wang Z, Guo TB, Park E, Sung E, et al. Abstract 5644: Claudin 18.2 × 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation. Cancer Res. 2020;80:5644–5644.
    1. Compte M, Harwood SL, Muñoz IG, Navarro R, Zonca M, Perez-Chacon G, et al. A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. Nat Commun. 2018;9:4809.
    1. Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019;11:eaav5989.
    1. Zappasodi R, Sirard C, Li Y, Budhu S, Abu-Akeel M, Liu C, et al. Rational design of anti-GITR-based combination immunotherapy. Nat Med. 2019;25:759–66.
    1. Veillette A, Chen J. SIRPα-CD47 immune checkpoint blockade in anticancer therapy. Trends Immunol. 2018;39:173–84.
    1. Sikic BI, Lakhani N, Patnaik A, Shah SA, Chandana SR, Rasco D, et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J Clin Oncol. 2019;37:946–53.
    1. Chen SH, Dominik PK, Stanfield J, Ding S, Yang W, Kurd N, et al. Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity. J Immunother Cancer. 2021;9:e003464.
    1. Cheng Y, Zhang T, Xu Q. Therapeutic advances in non-small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy. MedComm. 2021;2:692–729.
    1. Shum E, Reilley M, Najjar Y, Daud A, Thompson J, Baranda J, et al. 523 preliminary clinical experience with XmAb20717, a PD-1 × CTLA-4 bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer. 2021;9:A553–A553.
    1. Dovedi SJ, Elder MJ, Yang C, Sitnikova SI, Irving L, Hansen A, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1(+) activated T cells. Cancer Discov. 2021;11:1100–17.
    1. Hickingbottom B, Clynes R, Desjarlais J, Li C, Ding Y. Preliminary safety and pharmacodynamic (PD) activity of XmAB20717, a PD-1 × CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors. J Clin Oncol. 2020;38:e15001–e15001.
    1. Albiges L, Rodriguez LM, Kim S-W, Im S-A, Carcereny E, Rha SY, et al. Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): preliminary results from an FTIH trial. J Clin Oncol. 2022;40:107–107.
    1. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175–86.
    1. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–94.
    1. Du W, Yang M, Turner A, Xu C, Ferris RL, Huang J, et al. TIM-3 as a target for cancer immunotherapy and mechanisms of action. Int J Mol Sci. 2017;18:645.
    1. Deak LLC, Seeber S, Perro M, Weber P, Lauener L, Chen S, et al. Abstract 2270: RG7769 (PD1-TIM3), a novel heterodimeric avidity-driven T cell specific PD-1/TIM-3 bispecific antibody lacking Fc-mediated effector functions for dual checkpoint inhibition to reactivate dysfunctional T cells. Cancer Res. 2020;80:2270–2270.
    1. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.
    1. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172:5450–5.
    1. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107:7875–80.
    1. Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR, Pyle KJ, et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182:6659–69.
    1. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917–27.
    1. Lipson EJ, Tawbi HA-H, Schadendorf D, Ascierto PA, Matamala L, Gutiérrez EC, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047) J Clin Oncol. 2021;39:9503–9503.
    1. LaMotte-Mohs R, Shah K, Smith D, Gorlatov S, Ciccarone V, Tamura J, et al. Abstract 3217: MGD013, a bispecific PD-1 × LAG-3 dual-affinity re-targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment. Cancer Res. 2016;76:3217–3217.
    1. Kraman M, Fosh N, Kmiecik K, Everett K, Zimarino C, Faroudi M, et al. Abstract 2719: Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces CD8+ T-cell activation and modulates the tumor microenvironment to promote antitumor immune responses. Cancer Res. 2018;78:2719–2719.
    1. Kraman M, Faroudi M, Allen NL, Kmiecik K, Gliddon D, Seal C, et al. FS118, a bispecific antibody targeting LAG-3 and PD-L1, enhances T-cell activation resulting in potent antitumor activity. Clin Cancer Res. 2020;26:3333–44.
    1. Sung E, Ko M, Won JY, Jo Y, Park E, Kim H, et al. LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation. Mol Ther. 2022;30:2800–16.
    1. Park E, Kim H, Sung E, Jung U, Hong Y, Lee H, et al. Abstract 1633: ABL501, PD-L1 × LAG-3, a bispecific antibody promotes enhanced human T cell activation through targeting simultaneously two immune checkpoint inhibitors, LAG-3 and PD-L1. Cancer Res. 2021;81:1633–1633.
    1. Rodriguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE) J Clin Oncol. 2020;38:9503–9503.
    1. Mu S, Liang Z, Wang Y, Chu W, Chen YL, Wang Q, et al. PD-L1/TIGIT bispecific antibody showed survival advantage in animal model. Clin Transl Med. 2022;12:e754.
    1. Zeng T, Cao Y, Jin T, Tian Y, Dai C, Xu F. The CD112R/CD112 axis: a breakthrough in cancer immunotherapy. J Exp Clin Cancer Res. 2021;40:285.
    1. Dai S, Huang W, Yuan Z, Peng S, Si J, Wang C, et al. Abstract 5525: An Fc-competent bispecific antibody targeting PD-L1 and TIGIT induces strong immune responses and potent anti-tumor efficacy. Cancer Res. 2022;82:5525–5525.
    1. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18:155.
    1. Clouthier DL, Watts TH. Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection. Cytokine Growth Factor Rev. 2014;25:91–106.
    1. Balmanoukian AS, Infante JR, Aljumaily R, Naing A, Chintakuntlawar AV, Rizvi NA, et al. Safety and clinical activity of MEDI1873, a novel GITR agonist, in advanced solid tumors. Clin Cancer Res. 2020;26:6196–203.
    1. Wang B, Zhang W, Jankovic V, Golubov J, Poon P, Oswald EM, et al. Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8(+) T cell dysfunction and maintain memory phenotype. Sci Immunol. 2018;3:eaat7061.
    1. Chan S, Belmar N, Ho S, Rogers B, Stickler M, Graham M, et al. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy. Nat Cancer. 2022;3:337–354.
    1. Fritzell S, Levin M, Åberg I, Johansson M, Winnerstam M, Smith KE, et al. ATOR-1144 is a tumor-directed CTLA-4 × GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells. Cancer Res. 2019;79:4077.
    1. Jeong S, Park SH. Co-stimulatory receptors in cancers and their implications for cancer immunotherapy. Immune Netw. 2020;20:e3.
    1. Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol. 2021;18:715–27.
    1. Segal NH, Gopal AK, Bhatia S, Kohrt HE, Levy R, Pishvaian MJ, et al. A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer. J Clin Oncol. 2014;32:3007–3007.
    1. Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, Hamid O, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017;23:1929–36.
    1. Jeong S, Park E, Kim HD, Sung E, Kim H, Jeon J, et al. Novel anti-4-1BBxPD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade. J Immunother Cancer. 2021;9:e002428.
    1. Muik A, Altintas I, Kosoff R, Gieseke F, Schödel K, Salcedo T, et al. 561 DuoBody®-PD-L1×4–1BB (GEN1046) induces superior immune-cell activation, cytokine production and cytotoxicity by combining PD-L1 blockade with conditional 4–1BB co-stimulation. J Immunother Cancer. 2020;8:A338–9.
    1. Muik A, Garralda E, Altintas I, Gieseke F, Geva R, Ben-Ami E, et al. Preclinical characterization and phase I trial results of a bispecific antibody targeting PD-L1 and 4-1BB (GEN1046) in patients with advanced refractory solid tumors. Cancer Discov. 2022;12:1248–65.
    1. Polesso F, Sarker M, Weinberg AD, Murray SE, Moran AE. Ox40 agonist tumor immunotherapy does not impact regulatory T cell suppressive function. J Immunol. 2019;203:2011–9.
    1. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9:e89350.
    1. Kuang Z, Pu P, Wu M, Wu Z, Wang L, Li Y, et al. A novel bispecific antibody with PD-L1-assisted OX40 activation for cancer treatment. Mol Cancer Ther. 2020;19:2564–74.
    1. Perez-Santos M, Anaya-Ruiz M, Herrera-Camacho I, Millan-Perez Pena L, Rosas-Murrieta NH. Bispecific anti-OX40/CTLA-4 antibodies for advanced solid tumors: a patent evaluation of WO2018202649. Expert Opin Ther Pat. 2019;29:921–4.
    1. Amatore F, Gorvel L, Olive D. Role of inducible Co-stimulator (ICOS) in cancer immunotherapy. Expert Opin Biol Ther. 2020;20:141–50.
    1. Hanson A, Elpek K, Duong E, Shallberg L, Fan M, Johnson C, et al. ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models. PLoS One. 2020;15:e0239595.
    1. Maio M, Groenland SL, Bauer T, Rischin D, Gardeazabal I, Moreno V, et al. 1971P - Pharmacokinetic/pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study. Ann Oncol. 2019;30:v793.
    1. Sainson RC, Parveen N, Borhis G, Kosmac M, OKell T, Taggart E, et al. Abstract LB-153: KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo. Cancer Res. 2018;78:LB-153
    1. Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009;69:5627–9.
    1. Ellmark P, Hägerbrand K, Levin M, Schantz LV, Deronic A, Varas L, et al. 858 a bispecific antibody targeting CD40 and EpCAM induces superior anti-tumor effects compared to the combination of the monospecific antibodies. J Immunother Cancer. 2020;8:A511.
    1. Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer. 2021;21:181–97.
    1. Li L, Deng L, Meng X, Gu C, Meng L, Li K, et al. Tumor-targeting anti-EGFR × anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing. Transl Oncol. 2021;14:100916.
    1. Gu CL, Zhu HX, Deng L, Meng XQ, Li K, Xu W, et al. Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition. Acta Pharmacol Sin. 2022;43:672–80.
    1. Coward J, Mislang ARA, Frentzas S, Lemech CR, Nagrial A, Jin X, et al. Safety and efficacy of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors in a phase I dose escalation study. J Clin Oncol. 2021;39:2515.
    1. Coward J, Frentzas S, Mislang A, Gao B, Lemech C, Jin X, et al. 427 efficacy and safety of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with platinum-resistant/refractory epithelial ovarian cancer in a phase 1 study. J Immunother Cancer. 2021;9:A457.
    1. Chen X, Wang L, Li P, Song M, Qin G, Gao Q, et al. Dual TGF-beta and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma. Int J Cancer. 2018;143:2561–74.
    1. Yi M, Zhang J, Li A, Niu M, Yan Y, Jiao Y, et al. The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-beta and PD-L1. J Hematol Oncol. 2021;14:27.
    1. Ji J, Shen L, Li Z, Xu N, Liu T, Chen Y, et al. AK104 (PD-1/CTLA-4 bispecific) combined with chemotherapy as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: updated results from a phase Ib study. J Clin Oncol. 2021;39:232.
    1. Bai L, Sun M, Xu A, Bai Y, Wu J, Shao G, et al. Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma. J Clin Oncol. 2021;39:4101.
    1. Stein MN, Dorff TB, Goodman OB, Thomas RA, Silverman MH, Guo M, et al. A phase 2, multicenter, parallel-group, open-label study of vudalimab (XmAb20717), a PD-1 × CTLA-4 bispecific antibody, alone or in combination with chemotherapy or targeted therapy in patients with molecularly defined subtypes of metastatic castration-resistant prostate cancer. J Clin Oncol. 2022;40:TPS5097
    1. Sharma M, Sanborn RE, Cote GM, Bendell JC, Kaul S, Chen F, et al. 1020O a phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 × CTLA-4 DART® molecule in patients with advanced solid tumours. Ann Oncol. 2020;31:S704–5.
    1. Hellmann MD, Bivi N, Calderon B, Shimizu T, Delafontaine B, Liu ZT, et al. Safety and immunogenicity of LY3415244, a bispecific antibody against TIM-3 and PD-L1, in patients with advanced solid tumors. Clin Cancer Res. 2021;27:2773–81.
    1. Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24–34.
    1. Luke JJ, Patel MR, Hamilton EP, Chmielowski B, Ulahannan SV, Kindler HL, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms. J Clin Oncol. 2020;38:3004.
    1. Patel M, Luke J, Hamilton E, Chmielowski B, Blumenschein G, Kindler H, et al. 313 a phase 1 evaluation of tebotelimab, a bispecific PD-1 × LAG-3 DART® molecule, in combination with margetuximab in patients with advanced HER2+ neoplasms. J Immunother Cancer. 2020;8:A193.
    1. Wang J, Asch AS, Hamad N, Weickhardt A, Tomaszewska-Kiecana M, Dlugosz-Danecka M, et al. A phase 1, open-label study of MGD013, a bispecific DART® molecule binding PD-1 and LAG-3 in patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2020;136:21–2.
    1. Yap T, Wong D, Hu-Lieskovan S, Papadopoulos K, Morrow M, Grabowska U, et al. 395 a first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy. J Immunother Cancer. 2020;8:A240.
    1. Zhang J, Guo Y. A phase I study to evaluate the tolerance, safety, pharmacokinetic characteristics and preliminary efficacy of PM1022 in patients with advanced tumors and a phase IIA study to investigate the efficacy of PM1022 in patients with advanced tumors. 2022. Jun 01, .
    1. Attarwala H. TGN1412: from discovery to disaster. J Young Pharm. 2010;2:332–6.
    1. Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134) Ann Rev Immunol. 2010;28:57–78.
    1. Yachnin J, Ullenhag GJ, Carneiro A, Nielsen D, Rohrberg KS, Kvarnhammar AM, et al. A first-in-human phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 × OX40 bispecific antibody. J Clin Oncol. 2020;38:3061.
    1. Wang J, Sun Y, Chu Q, Duan J, Wan R, Wang Z, et al. Abstract CT513: phase I study of IBI322 (anti-CD47/Pd-L1 bispecific antibody) monotherapy therapy in patients with advanced solid tumors in China. Cancer Res. 2022;82:CT513
    1. Zhou C, Ren S, Luo Y, Wang L, Xiong A, Su C, et al. A phase IB/II study of AK112, a PD-1/VEGF bispecific antibody, as first- or second-line therapy for advanced non–small cell lung cancer (NSCLC) J Clin Oncol. 2022;40:9040.
    1. Zhao Y, Fang W, Yang Y, Chen J, Zhuang L, Du Y, et al. A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer. J Clin Oncol. 2022;40:9019.
    1. Herpers B, Eppink B, James MI, Cortina C, Cañellas-Socias A, Boj SF, et al. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nat Cancer. 2022;3:418–36.
    1. Wu L, Seung E, Xu L, Rao E, Lord DM, Wei RR, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer. 2020;1:86–98.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir