A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy

Abstract

Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses toward HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared with monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced antitumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells. Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses toward HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared with monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced antitumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells. Human epidermal growth factor receptor-2 (HER2, HER2/neu, or human ERBB-2) belongs to a family of four-transmembrane receptors involved in the regulation of cell growth and differentiation (1Harbeck N. Pegram M.D. Ruschoff J. Mobus V. Targeted therapy in metastatic breast cancer: The HER2/neu oncogene.Breast Care (Basel). 2010; 5: 3-7Crossref PubMed Scopus (15) Google Scholar). HER2 is overexpressed in multiple solid tumors including breast (BC), colorectal (CRC), gastric (GC), gastroesophageal junction (GEJC), non-small-cell lung (NSCLC), biliary tract (BTC), and bladder cancers. The emergence of trastuzumab (Herceptin), a widely used monoclonal antibody (mAb) therapy that blocks HER2 signaling and induces antibody-dependent cell-mediated cytotoxicity (ADCC) toward HER2+ tumors, has significantly improved the survival rate of HER2+ carcinoma patients (2Li Q. Lv M. Jiang H. Wang Y. Yu S. Li W. Yu Y. Liu T. A prospective observational study on the optimal maintenance strategy in HER2-positive advanced gastric cancer treated with trastuzumab-based therapy.J. Cancer Res. Clin. Oncol. 2020; 146: 287-295Crossref PubMed Scopus (9) Google Scholar, 3Macpherson I.R. Spiliopoulou P. Rafii S. Saggese M. Baird R.D. Garcia-Corbacho J. Italiano A. Bonneterre J. Campone M. Cresti N. Posner J. Takeda Y. Arimura A. Spicer J. A phase I/II study of epertinib plus trastuzumab with or without chemotherapy in patients with HER2-positive metastatic breast cancer.Breast Cancer Res. 2019; 22: 1Crossref PubMed Scopus (13) Google Scholar, 4Cameron D. Piccart-Gebhart M.J. Gelber R.D. 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Oncog. 2012; 17: 1-16Crossref PubMed Scopus (235) Google Scholar). Known causes of trastuzumab-induced drug resistance include downregulation of HER2, upregulation of PD-L1 expression in tumor cells, or mutations in the HER2-PI3K-AKT signaling pathway (7Valabrega G. Montemurro F. Aglietta M. Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer.Ann. Oncol. 2007; 18: 977-984Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 8Chaganty B.K.R. Qiu S. Gest A. Lu Y. Ivan C. Calin G.A. Weiner L.M. Fan Z. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNgamma secretion.Cancer Lett. 2018; 430: 47-56Crossref PubMed Scopus (59) Google Scholar, 9Turcotte M. Allard D. Mittal D. Bareche Y. Buisseret L. Jose V. Pommey S. Delisle V. Loi S. Joensuu H. Kellokumpu-Lehtinen P.L. Sotiriou C. Smyth M.J. Stagg J. CD73 promotes resistance to HER2/ErbB2 antibody therapy.Cancer Res. 2017; 77: 5652-5663Crossref PubMed Scopus (68) Google Scholar). PD-L1 is highly expressed in various types of tumor cells, and its counter receptor PD-1 is typically expressed in various immune cells, such as tumor infiltrating T cells. Their interaction mediates different mechanisms of immune escape, including T cell apoptosis, functional inhibition, and exhaustion (10Blank C. Gajewski T.F. Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy.Cancer Immunol. Immunother. 2005; 54: 307-314Crossref PubMed Scopus (415) Google Scholar, 11Wherry E.J. T cell exhaustion.Nat. Immunol. 2011; 12: 492-499Crossref PubMed Scopus (2275) Google Scholar, 12Zou W. Chen L. Inhibitory B7-family molecules in the tumour microenvironment.Nat. Rev. Immunol. 2008; 8: 467-477Crossref PubMed Scopus (1191) Google Scholar, 13Gibbons R.M. Liu X. 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Immune signatures following single dose trastuzumab predict pathologic response to PreoperativeTrastuzumab and chemotherapy in HER2-positive early breast cancer.Clin. Cancer Res. 2016; 22: 3249-3259Crossref PubMed Scopus (52) Google Scholar). It is thus believed that the upregulation of PD-L1 is, at least partially, the cause for induced drug resistance of HER2+ tumors to trastuzumab. The clinical benefits of antagonistic mAbs against PD-1 or PD-L1 have been demonstrated in a variety of human cancers (15Herbst R.S. Baas P. Kim D.W. Felip E. Perez-Gracia J.L. Han J.Y. Molina J. Kim J.H. Arvis C.D. Ahn M.J. Majem M. Fidler M.J. de Castro Jr., G. Garrido M. Lubiniecki G.M. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4242) Google Scholar, 16Schachter J. Ribas A. Long G.V. Arance A. Grob J.J. Mortier L. Daud A. Carlino M.S. McNeil C. Lotem M. Larkin J. Lorigan P. Neyns B. Blank C. Petrella T.M. et al.Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).Lancet. 2017; 390: 1853-1862Abstract Full Text Full Text PDF PubMed Scopus (726) Google Scholar, 17Bertucci F. Goncalves A. Immunotherapy in breast cancer: The emerging role of PD-1 and PD-L1.Curr. Oncol. Rep. 2017; 19: 64Crossref PubMed Scopus (75) Google Scholar). However, a substantial number of patients fail to respond to anti-PD-1 or anti-PD-L1 monotherapies (18Pitt J.M. Vetizou M. Daillere R. Roberti M.P. Yamazaki T. Routy B. Lepage P. Boneca I.G. Chamaillard M. Kroemer G. Zitvogel L. Resistance mechanisms to immune-checkpoint blockade in cancer: Tumor-intrinsic and -extrinsic factors.Immunity. 2016; 44: 1255-1269Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 19Nowicki T.S. Hu-Lieskovan S. Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade.Cancer J. 2018; 24: 47-53Crossref PubMed Scopus (195) Google Scholar). Preclinical and clinical data have demonstrated the effectiveness of trastuzumab and anti-PD-1 combination therapy in managing HER2+ cancers (20Loi S. Giobbie-Hurder A. Gombos A. Bachelot T. Hui R. Curigliano G. Campone M. Biganzoli L. Bonnefoi H. Jerusalem G. Bartsch R. Rabaglio-Poretti M. Kammler R. Maibach R. Smyth M.J. et al.Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial.Lancet Oncol. 2019; 20: 371-382Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 21Muller P. Kreuzaler M. Khan T. Thommen D.S. Martin K. Glatz K. Savic S. Harbeck N. M. H. S. M. A. Trastuzumab HER2+ breast cancer highly to PubMed Scopus Google Scholar, B. C. P. M. A. et and trastuzumab in HER2-positive or junction cancer: single-arm, phase 2 trial.Lancet Oncol. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). In HER2+ metastatic BC a combination of trastuzumab, and chemotherapy in clinical responses (20Loi S. Giobbie-Hurder A. Gombos A. Bachelot T. Hui R. Curigliano G. Campone M. Biganzoli L. Bonnefoi H. Jerusalem G. Bartsch R. Rabaglio-Poretti M. Kammler R. Maibach R. Smyth M.J. et al.Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial.Lancet Oncol. 2019; 20: 371-382Abstract Full Text Full Text PDF PubMed Scopus (212) Google the of targeting HER2 and PD-1/PD-L1 signaling pathways antibodies that or by are a of cancer The of and combination therapies include on or signaling to tumor both effector cells to tumor drug resistance by downregulation of either D. in antibody for Rev. 2019; PubMed Scopus Google Scholar, to the of 2016; PubMed Scopus Google Scholar, E. S. S. et strategy for against 2016; PubMed Scopus Google Scholar). are on the and of in the are in the preclinical or clinical J.M. P. A of the Rev. 2019; 18: PubMed Scopus Google Scholar). of have been to BsAb M.J. and of bispecific PubMed Scopus Google Scholar, de de A of bispecific antibodies and antibody in and clinical 2019; PubMed Scopus Google including which a targeting and a targeting a different or de de A of bispecific antibodies and antibody in and clinical 2019; PubMed Scopus Google Scholar). are from the of the and of mAbs or from antibody The of bispecific 2017; PubMed Scopus Google Scholar). The of can and M. Wang C. D. Wang J. E. S. A. Wang X. Liu D. and analysis of bispecific antibody 2018; PubMed Scopus Google of the may the and of BsAb molecules J. A. J. A. R. M. J. E. W. J. W. C. G. N. M. et of bispecific antibodies with activity against monoclonal 2011; PubMed Scopus Google potentially in of activity S. J. C. G. A. A. F. of by on the activity of a antibody against 12: PubMed Scopus Google Scholar). targeting HER2 and PD-1 have been reported and show antitumor activities in models C.L. Zhu L. Li K. W. L. Liu Zhu antibody simultaneously targeting and HER2 tumor growth direct tumor cell in combination with blockade and HER2 Scopus Google Scholar). However, both molecules IgG1 as which may clinical effector such as cytotoxicity and antibody-dependent to the antitumor activities by trastuzumab, can cause to immune cells, T cells. In we a HER2/PD-L1 BsAb with trastuzumab in IgG1 subclass to humanized anti-PD-L1 BsAb enhanced to tumor cells when compared with trastuzumab. In the late phase of tumor xenograft the BsAb showed superior tumor inhibition compared with and combination through the inhibition of HER2 blockade of and enhanced Therefore, simultaneously targeting both HER2 and PD-L1 molecules with BsAb strategy may a highly effective for trastuzumab-resistant HER2+ The HER2/PD-L1 BsAb was constructed with trastuzumab IgG1 and anti-PD-L1 in the of expression and BsAb was by and BsAb displayed and in we the of BsAb to and cynomolgus and PD-L1 We of BsAb to human and cynomolgus and PD-L1 to or PD-L1 A and BsAb can simultaneously to both was with the results that trastuzumab, was of to HER2 and PD-L1 at the We the of BsAb to HER2 and PD-L1 The of BsAb and trastuzumab to HER2 and of to human PD-L1 was that of was to the of BsAb to PD-L1 and PD-1 interaction BsAb and the of human PD-1 to PD-L1 at with of and was to the activities of BsAb at T cells. cells with T cells from different to T cell activation and of such as BsAb and the was the at of both 10 and a was at and human T cell was used to BsAb at the in T cell was significantly by with BsAb and the the of PD-L1 Therefore, BsAb enhanced the of PD-L1 to T cells in different We cells to the of BsAb to HER2+ tumor cells in vitro. BsAb and trastuzumab effective in cell and the to be and of the mechanisms of of trastuzumab is S. monoclonal and Clin. Oncol. 2010; PubMed Scopus Google and as we compared the of BsAb and trastuzumab in human as effector cells and HER2+ and tumor cells as cells. BsAb trastuzumab in both cell cells PD-L1 A and we found that trastuzumab treatment in the of the of with either tumor cell and treatment the expression of PD-L1 in both and cells data that the HER2/PD-L1 BsAb through upregulation of PD-L1 expression in both and tumor cells. BsAb with we human peripheral blood mononuclear cells to immune in on which tumor xenograft was we compared the antitumor activities of BsAb and trastuzumab in the tumor xenograft BsAb and trastuzumab inhibition of tumor BsAb displayed antitumor activities to trastuzumab in the early phase of the the in the late phase of the we the antitumor activities of BsAb in HER2 and PD-L1 tumor xenograft BsAb significantly tumor growth inhibition in to trastuzumab and combination therapy on and and to the xenograft was no trastuzumab, and combination in the early phase of the the BsAb treatment and the to in tumor in to the in or toxicity Therefore, in vivo results that BsAb is superior to trastuzumab or the combination therapy in PD-L1 positive or human BsAb was administered mg/kg single cynomolgus monkeys, blood at and serum of BsAb by BsAb the of antibodies and its serum was at the In no or of BsAb in cynomolgus and as by blood and cell Trastuzumab has been in patients with various solid tumors HER2 mutations Y. the Rev. PubMed Scopus Google Scholar, HER2-targeted therapies a role breast Rev. Clin. Oncol. 2020; 17: PubMed Scopus Google Scholar). its in and have been in HER2+ cancer types such as or bladder cancers E. HER2 therapy for Oncol. PubMed Scopus Google Scholar, D. C. Harris L. H. G. H. D. C.L. P. L. Winer E. C. phase of compared with for metastatic breast with trastuzumab for and to trastuzumab or in Final results of cancer and Clin. Oncol. 2008; PubMed Scopus Google Scholar). The responses of solid tumors to trastuzumab may be due to the in the levels of HER2 of of the a variety of are including S. D. Gianni L. Krop I.E. M. Baselga J. Pegram M. V. E. L. Lu S. K. Trastuzumab for HER2-positive advanced breast J. 2012; PubMed Scopus Google Scholar, Trastuzumab 2020; PubMed Scopus Google and such as and L. Han X. therapy of human cancer: and Clin. PubMed Scopus Google Scholar, D. J. W. Du Y. J. Yang J. X. P. Yang F. and pharmacokinetics results of a HER2 bispecific antibody in patients with HER2-positive metastatic breast Clin. Oncol. 2020; PubMed Google Scholar, A. H. H. Wang L. Z. H. S. M. Y. de E. resistance to HER2-targeted therapy with a bispecific 2017; PubMed Scopus Google Scholar, Li J. J. M. R. D. Wang Li Y. M. Li G. J. E. G. E. C. et of a bispecific antibody that HER2 and T Res. PubMed Scopus Google therapeutic are to induced or intrinsic drug resistance to A number of have demonstrated that HER2-targeted therapies can upregulation of PD-L1 expression in HER2+ tumors J.H. Kim Han A. Kim Kim Kim Kim Kim J.H. S.M. et or HER2 inhibition the tumor by of PD-L1 and 2017; 8: PubMed Scopus Google Scholar). have reported that the combination of trastuzumab and clinical benefits in HER2+ and the that upregulation of PD-L1 to resistance to trastuzumab (20Loi S. Giobbie-Hurder A. Gombos A. Bachelot T. Hui R. Curigliano G. Campone M. Biganzoli L. Bonnefoi H. Jerusalem G. Bartsch R. Rabaglio-Poretti M. Kammler R. Maibach R. Smyth M.J. et al.Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial.Lancet Oncol. 2019; 20: 371-382Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, B. C. P. M. A. et and trastuzumab in HER2-positive or junction cancer: single-arm, phase 2 trial.Lancet Oncol. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). In we constructed a HER2/PD-L1 BsAb in the IgG1 subclass with the of HER2 therapy with immune PD-1/PD-L1 therapy to HER2-overexpressing solid We the trastuzumab-induced drug resistance with the late phase of xenograft tumor HER2/PD-L1 BsAb demonstrated and combination targeting HER2 and PD-L1 Therefore, HER2/PD-L1 are to solid tumors both HER2 and PD-L1 and to tumor resistance to therapies both in the IgG1 have been with clinical C.L. Zhu L. Li K. W. L. Liu Zhu antibody simultaneously targeting and HER2 tumor growth direct tumor cell in combination with blockade and HER2 Scopus Google Scholar). HER2/PD-L1 different from that of and may patients clinical IgG1 in trastuzumab is a of and N. F. M.J. J. Trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in breast cancer cell Oncol. 2012; Full Text Full Text PDF PubMed Scopus Google by cells and to HER2+ tumor cells. In the of IgG1 may cause to T cells. in or can to T cells, are to and be potentially by HER2/PD-L1 in the IgG1 PD-L1 is expressed in tumor cells. The of strategy is that HER2/PD-L1 T cells to HER2-expressing human cells be in the tumor xenograft the of the antitumor and of HER2/PD-L1 in IgG1 are superior to that of BsAb in which is at is to be is of the of trastuzumab. HER2/PD-L1 BsAb displayed trastuzumab to to tumor cells. We enhanced was et (8Chaganty B.K.R. Qiu S. Gest A. Lu Y. Ivan C. Calin G.A. Weiner L.M. Fan Z. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNgamma secretion.Cancer Lett. 2018; 430: 47-56Crossref PubMed Scopus (59) Google previously reported that targeting HER2 with trastuzumab PD-L1 expression in tumor cells by in the tumor to induced immune resistance to HER2 In we demonstrated that trastuzumab induced the of in the of with both and tumor cell in the of PD-L1 expression in both tumor cell that a the of BsAb was enhanced of the upregulation of PD-L1 on the tumor cell Thus, we that trastuzumab treatment in cancer trastuzumab which tumors tumors, immune by T and cells. preclinical results that the of HER2/PD-L1 BsAb potentially and thus clinical benefits in tumor xenograft In HER2/PD-L1 BsAb in the IgG1 subclass the activities of both mAbs and demonstrated enhanced to HER2+ tumor cells. In the late of the xenograft tumor its therapeutic was superior to and combination HER2/PD-L1 BsAb was potentially effective option for managing HER2+ trastuzumab-resistant and cells from the and serum from and from Trastuzumab and humanized anti-PD-L1 in was from Human antibody and by and from and of was from Human was from was from was from was from A from was from was from was from was from Human from cells mAbs against human PD-L1 in a different was from cells, and of the PD-L1 antibody by was humanized a strategy with human and The was as previously E. S. S. et strategy for against 2016; PubMed Scopus Google and in the of humanized antibody and as by A was anti-PD-L1 and to increase the of molecules to the of 2016; PubMed Scopus Google Scholar). Trastuzumab and from the was to the of trastuzumab The and a and in E. cells the the cells in in expression of the was and the antibodies A The antibodies against and at The of BsAb interaction with and from different was with 2 at of BsAb and antibodies and to was and for 1 at The was and with was at a protein was at The with for 1 with in and with of antibodies for at The and with 2 protein for 1 at was and for 1 at The and the with was at a to 10 and in and to of BsAb with and was on in the at BsAb was A and from to rate and the The of BsAb to the and PD-L1 interaction was a In protein was at of BsAb and trastuzumab to the with 1 of a the and with The of antibodies was on a HER2 and PD-L1 expression levels in and human cancer cells by In with trastuzumab and in the cells with antibody and by a PD-L1 expression tumor cells cell at and with different of or for at in cancer cell and the expression levels of PD-L1 by as was used to the of of was of antibody at and on a analysis was to the purity, and of with on a was at at with a rate of and of Human blood from human with a and in for in and to cells T cells and in the or of or of cell to with 1 1 and human PD-L1 cell at with either or with and T cells with cell positive to T cells in in the or of antibodies at the for at in with cells a cells at of BsAb and trastuzumab in to the The in a for at was and the cells was as the of growth to cells. The from the of on a Human from the by with to cells from human with and cells and cells in the or of for was by the cell was to the of by cells administered to the of on with and administered the of on The tumor was the to on tumor as mg/kg mg/kg mg/kg trastuzumab mg/kg anti-PD-L1 10 mg/kg on and was a and as cells administered to the of on in administered to the of on The tumor was the to on tumor mg/kg 10 mg/kg and mg/kg trastuzumab. on and and as by the of In a serum cynomolgus with 10 mg/kg blood in at and of BsAb in cynomolgus the by was and with of HER2 protein was and for 1 was with The was a on and for toxicity with a and by the of was multiple by multiple was In both was are as in the data are the and the data are to be Y. X. and X. D. from G. L. and C. W. are of The to and from of of and for of was by the and for and the of the of and the of and of and of and for and of and the and and of and We for its the of C. and F. C. and F. data X. L. and Y. H. Y. X. G. and X. D. Y. 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