Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of MSB2311, a novel pH-dependent anti-PD-L1 monoclonal antibody, treating patients with advanced solid tumors and lymphoma

  • Research
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

MSB2311 is a novel pH-dependent humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody. This phase I study primarily aimed to determine the maximum tolerated dose (MTD)/recommended phase 2 dose level (RP2D) of MSB2311 in patients with advanced solid tumors or lymphoma. MSB2311 was intravenously administered at 3, 10, and 20 mg/kg every 3 weeks (Q3W) and 10 mg/kg every 2 weeks (Q2W) using 3 + 3 design. During expansion phase, eligible patients with either PD-L1 overexpression, Epstein-Barr Virus positive, microsatellite instability high/mismatch repair deficient, or high tumor mutation burden tumors were treated at RP2D. A total of 37 Chinese patients were treated, including 31 with solid tumors and 6 lymphoma. No dose limiting toxicity was reported and MTD was not reached. The trial was expanded at 20 mg/kg Q3W or 10 mg/kg Q2W, both of which were determined as RP2D. Most common drug-related treatment-emergent adverse events were anemia (43.2%), aspartate aminotransferase increase (27.0%), proteinuria (21.6%), alanine aminotransferase increase and hypothyroidism (18.9% each), thyroid stimulating hormone increased and hyperglycemia (16.2% each). Out of 20 efficacy evaluable patients with biomarker positive solid tumors, 6 achieved confirmed partial response with the median duration of response of 11.0 months (95% CI 7.0–11.4) and 4 had stable disease, resulting an objective response rate of 30.0% (95% CI 11.9, 54.3) and disease control rate of 50.0% (95% CI 27.2, 72.8). One partial response was also observed among 6 patients with lymphoma. MSB2311 demonstrated a manageable safety profile and promising antitumor activity in patients with advanced solid tumors and lymphomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Research data are not shared.

Abbreviations

ADA:

Antidrug antibody

CL:

Clearance

DCR:

Disease control rate

DLT:

Dose-limiting toxicities

dMMR:

Mismatch repair deficient

DoR:

Duration of response

EES:

Efficacy evaluable set

FAS:

Full analysis set

ICIs:

Checkpoint inhibitors

IWG:

International working group

MAD:

Maximum administered dose

MSI-H:

Microsatellite instability-high

NCI-CTCAE:

National Cancer Institute common terminology criteria for adverse events

ORR:

Objective response rate

PD:

Progressive disease

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PK:

Pharmacokinetic

PR:

Partial response

RP2D:

Recommended phase 2 dose

SD:

Stable disease

TMB-H:

High tumor mutation burden

References

  1. Zou W, Wolchok JD, Chen L (2016) PD-L1 (B7–H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 8(328):328rv4

    Article  PubMed  PubMed Central  Google Scholar 

  2. Xia L, Liu Y, Wang Y (2019) PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer: current status and future directions. Oncologist 24(Suppl 1):S31–S41

    Article  PubMed  PubMed Central  Google Scholar 

  3. Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856

    Article  CAS  PubMed  Google Scholar 

  4. Chang L, Chang M, Chang HM, Chang F (2018) Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol 26(2):e15–e21

    Article  CAS  PubMed  Google Scholar 

  5. Rodriquenz MG, Roviello G, D’Angelo A, Lavacchi D, Roviello F, Polom K (2020) MSI and EBV positive gastric cancer’s subgroups and their link with novel immunotherapy. J Clin Med 9(5):1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chan TA, Yarchoan M, Jaffee E et al (2019) Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 30(1):44–56

    Article  CAS  PubMed  Google Scholar 

  7. Xueming Q, Fei T, Huanhuan G, Zhen L, Xiao-Feng Q (2017) Characterization of a humanized PD-L1 blocking antibody with pH-dependent antigen binding in a humanized syngenic tumor model. J Clin Oncol 35(7_suppl):81–81

    Article  Google Scholar 

  8. Xichun H, Jifang G, Dongmei J et al (2020) MSB2311, an anti-programmed death-ligand 1 antibody, in advanced solid tumors and hematological malignancies: Safety and tolerability, early anti-cancer activities from a phase I study in Chinese patients. J Clin Oncol 38(15_suppl):e15011–e15011

    Article  Google Scholar 

  9. Lin S, Jifang G, Jian Z et al (2021) Updated safety and efficacy of MSB2311 (an anti-programmed death-ligand 1 antibody) in Chinese patients with advanced solid tumors and hematological malignancies from a phase 1 study. J Clin Oncol 39(15_suppl):e14547–e14547

    Article  Google Scholar 

  10. Igawa T, Ishii S, Tachibana T et al (2010) Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 28(11):1203–1207

    Article  CAS  PubMed  Google Scholar 

  11. Klaus T, Deshmukh S (2021) pH-responsive antibodies for therapeutic applications. J Biomed Sci 28(1):11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baraibar I, Melero I, Ponz-Sarvise M, Castanon E (2019) Safety and tolerability of immune checkpoint inhibitors (PD-1 and PD-L1) in cancer. Drug Saf 42(2):281–294

    Article  CAS  PubMed  Google Scholar 

  13. Johnson DB, Chandra S, Sosman JA (2018) Immune checkpoint inhibitor toxicity in 2018. JAMA 320(16):1702–1703

    Article  PubMed  Google Scholar 

  14. Deng R, Bumbaca D, Pastuskovas CV et al (2016) Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. MAbs 8(3):593–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu D, Ma C, Lu P et al (2021) Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma. Eur J Cancer 148:1–13

    Article  CAS  PubMed  Google Scholar 

  16. Marabelle A, Fakih M, Lopez J et al (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21(10):1353–1365

    Article  CAS  PubMed  Google Scholar 

  17. Marabelle A, Le DT, Ascierto PA et al (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 38(1):1–10

    Article  CAS  PubMed  Google Scholar 

  18. Kim ST, Cristescu R, Bass AJ et al (2018) Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 24(9):1449–1458

    Article  CAS  PubMed  Google Scholar 

  19. Panda A, Mehnert JM, Hirshfield KM et al (2018) Immune activation and benefit from avelumab in EBV-positive gastric cancer. J Natl Cancer Inst 110(3):316–320

    Article  CAS  PubMed  Google Scholar 

  20. Ren D, Hua Y, Yu B et al (2020) Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. Mol Cancer 19(1):19

    Article  PubMed  PubMed Central  Google Scholar 

  21. Camidge DR, Doebele RC, Kerr KM (2019) Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC. Nat Rev Clin Oncol 16(6):341–355

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the patients, their families, the investigators, and the teams who participated in this trial. We thank all the investigators and site staff working on this trial. We acknowledge the contribution made by Li Xu, John Huang, Liren Xiao, Alan Lin, Linlin Mao, Steven Yu and Ling Sun from Transcenta for the development of this manuscript.

Author information

Author notes

  1. Qi Zhang and Jian Zhang are co-first authors and contribute equally.

Authors and Affiliations

  1. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Fucheng Road 52, Haidian District, Beijing, 100142, China

    Qi Zhang, Jifang Gong, Lin Shen & Jian Li

  2. Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China

    Jian Zhang & Dongmei Ji

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Jian Zhang & Dongmei Ji

  4. Department of Colorectal Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China

    Haijun Zhong

  5. Department of Medical Oncology, Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Ying Yuan

  6. Department of Oncology, Nantong Tumor Hospital & Affiliated Tumor Hospital of Nantong University, Nantong, China

    Lei Yang

  7. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China

    Qingyuan Zhang

  8. Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, China

    Jing Li, Zhenling Yao, Chuan Qi, Jianming Wang, Lingmin Lu, Michael Shi & Xueming Qian

  9. Department of Breast and Urinary Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    Xichun Hu

  10. Department of Oncology, Shanghai Medical College, Fudan University, No. 270, Dong’an Road, Shanghai, 200032, China

    Xichun Hu

Authors
  1. Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haijun Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qingyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dongmei Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jifang Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhenling Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chuan Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jianming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lingmin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xueming Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lin Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xichun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XH, LS, XQ, MS and CQ conceived, designed and supervised the study. Data collection, management, analysis and interpretation were performed by JZ, HZ, YY, LY, QZ, DJ, JG, JL, ZY, JW, LL. The first draft of the manuscript was prepared by QZ, JZ, JL and JL. All authors reviewed and approved this manuscript.

Corresponding authors

Correspondence to Jian Li or Xichun Hu.

Ethics declarations

Conflict of interests

Jing Li, Zhenling Yao, Chuan Qi, Jianming Wang, Lingmin Lu, Michael Shi and Xueming Qian are employees of Transcenta Holding Limited and own stock of Transcenta. The other authors declare that they have no competing interests.

Ethical approval

This study was approved by the institutes' medical ethics committee and was conducted in accordance with the Declaration of Helsinki and guidelines for Good Clinical Practice. The study was registered at www.clinicaltrials.gov (NCT04272944).

Informed consent

Written informed consent was obtained from all patients prior to enrolment.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 17 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Zhang, J., Zhong, H. et al. Phase I study of MSB2311, a novel pH-dependent anti-PD-L1 monoclonal antibody, treating patients with advanced solid tumors and lymphoma. Cancer Immunol Immunother 72, 2729–2739 (2023). https://doi.org/10.1007/s00262-023-03434-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-023-03434-2

Keywords

Search

Navigation