Skip to main content

Advertisement

SpringerLink
Log in

Characterization of anti-CD79b/CD3 bispecific antibody, a potential therapy for B cell malignancies

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

Abstract

High rates of relapse and poor prognosis confer an urgent need for novel therapeutic agents for B cell non-Hodgkin lymphomas (B-NHLs). Herein, we describe a human IgG-like anti-CD79b/CD3 bispecific antibody (IBI38D9-L) that selectively depletes antigen-positive malignant B cells as an alternative treatment option for relapsed or refractory NHL patients. The antitumor activity and mechanism of action of IBI38D9-L were investigated in vitro using B-NHL cell lines and human primary effector cells and in vivo using xenograft models reconstituted with human PBMCs (peripheral blood mononuclear cells). Pharmacokinetic (PK) properties and preclinical toxicology were evaluated in cynomolgus monkeys and HSC-NPG mice. IBI38D9-L exerted potent B cell killing as well as T cell activation and proliferation in a tumor cell-dependent manner in vitro and was active against B-NHL cell lines with various CD79b expression levels. Subcutaneous xenograft tumors in NOG mice engrafted with human PBMCs were eradicated by IBI38D9-L treatment. Moreover, IBI38D9-L-treated mice showed a strong infiltration of activated T cells. In HSC-NPG mice, IBI38D9-L resulted in potent B cell depletion in peripheral blood and induced only slight body weight loss and cytokine release syndrome without significant toxicological findings. In cynomolgus monkeys, IBI38D9-L was well tolerated with good pharmacokinetic profiles. Collectively, these preclinical efficacy and safety data provide strong scientific rationales for using anti-CD79b/CD3 bispecific antibody as a promising therapeutic agent for B cell malignancies.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AAALAC:

Association for Assessment and Accreditation of Laboratory Animal Care International

ADC:

Antibody–drug conjugates

ALL:

Acute lymphoblastic leukemia

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

Bite:

Bispecific T cell engager

B-NHLs:

B cell non-Hodgkin lymphomas

BsAbs:

Bispecific antibodies

CBA:

Cytometric Bead Array

CREA:

Creatinine

CRS:

Cytokine release syndrome

DLBCL:

Diffuse large B cell lymphoma

FDA:

Food and Drug Administration

IFN:

Interferon

IL:

Interleukin

MFI:

Median fluorescence intensity

OCT:

Optimal cutting temperature

PBMCs:

Peripheral blood mononuclear cells

PBS:

Phosphate-buffered saline

PE:

Phycoerythrin

PK:

Pharmacokinetic

PLT:

Platelet

RBC:

Red blood cell

sIg:

Surface Ig

SPR:

Surface plasma resonance

TGI:

Tumor growth inhibition

TMDD:

Target-mediated drug disposition

TNF:

Tumor necrosis factor

WBC:

White blood cell

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71:7–33. https://doi.org/10.3322/caac.21654

    Article  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. https://doi.org/10.3322/caac.21338

    Article  Google Scholar 

  3. Ghielmini M (2005) Multimodality therapies and optimal schedule of antibodies: rituximab in lymphoma as an example. Hematol Am Soc Hematol Educ Program. https://doi.org/10.1182/asheducation-2005.1.321

    Article  Google Scholar 

  4. Shankland KR, Armitage JO, Hancock BW (2012) Non-Hodgkin lymphoma. Lancet 380:848–857. https://doi.org/10.1016/S0140-6736(12)60605-9

    Article  Google Scholar 

  5. Casulo C, Byrtek M, Dawson KL et al (2015) Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national lymphocare study. J Clin Oncol 33:2516–2522. https://doi.org/10.1200/JCO.2014.59.7534

    Article  CAS  Google Scholar 

  6. Gisselbrecht C, Glass B, Mounier N et al (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28:4184–4190. https://doi.org/10.1200/JCO.2010.28.1618

    Article  Google Scholar 

  7. Matsuuchi L, Gold MR (2001) New views of BCR structure and organization. Curr Opin Immunol 13:270–277. https://doi.org/10.1016/s0952-7915(00)00215-6

    Article  CAS  Google Scholar 

  8. Chu PG, Arber DA (2001) CD79: a review. Appl Immunohistochem Mol Morphol 9:97–106. https://doi.org/10.1097/00129039-200106000-00001

    Article  CAS  Google Scholar 

  9. Zomas AP, Matutes E, Morilla R, Owusu-Ankomah K, Seon BK, Catovsky D (1996) Expression of the immunoglobulin-associated protein B29 in B cell disorders with the monoclonal antibody SN8 (CD79b). Leukemia 10:1966–1970

    CAS  Google Scholar 

  10. Cabezudo E, Carrara P, Morilla R, Matutes E (1999) Quantitative analysis of CD79b, CD5 and CD19 in mature B-cell lymphoproliferative disorders. Haematologica 84:413–418

    CAS  Google Scholar 

  11. Dornan D, Bennett F, Chen Y et al (2009) Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 114:2721–2729. https://doi.org/10.1182/blood-2009-02-205500

    Article  CAS  Google Scholar 

  12. Ormhoj M, Scarfo I, Cabral ML et al (2019) Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without cotargeting CD19. Clin Cancer Res 25:7046–7057. https://doi.org/10.1158/1078-0432.CCR-19-1337

    Article  Google Scholar 

  13. Sun LL, Ellerman D, Mathieu M et al (2015) Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med 7:287ra70. https://doi.org/10.1126/scitranslmed.aaa4802

  14. Pillarisetti K, Edavettal S, Mendonca M et al (2020) A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood 135:1232–1243. https://doi.org/10.1182/blood.2019003342

    Article  CAS  Google Scholar 

  15. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA (2006) Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 43:763–771. https://doi.org/10.1016/j.molimm.2005.03.007

    Article  CAS  Google Scholar 

  16. Junttila TT, Li J, Johnston J et al (2014) Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Res 74:5561–5571. https://doi.org/10.1158/0008-5472.CAN-13-3622-T

    Article  CAS  Google Scholar 

  17. Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 99:306–314. https://doi.org/10.1016/j.cmpb.2010.01.007

    Article  Google Scholar 

  18. Hezareh M, Hessell AJ, Jensen RC, van de Winkel JG, Parren PW (2001) Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J Virol 75:12161–12168. https://doi.org/10.1128/JVI.75.24.12161-12168.2001

    Article  CAS  Google Scholar 

  19. Polson AG, Yu SF, Elkins K et al (2007) Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood 110:616–623. https://doi.org/10.1182/blood-2007-01-066704

    Article  CAS  Google Scholar 

  20. Caballero A, Katkere B, Wen XY, Drake L, Nashar TO, Drake JR (2006) Functional and structural requirements for the internalization of distinct BCR-ligand complexes. Eur J Immunol 36:3131–3145. https://doi.org/10.1002/eji.200636447

    Article  CAS  Google Scholar 

  21. Engelberts PJ, Hiemstra IH, de Jong B et al (2020) DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine 52:102625. https://doi.org/10.1016/j.ebiom.2019.102625

    Article  Google Scholar 

  22. Iwata Y, Sasaki M, Harada A et al (2019) Daily ascending dosing in cynomolgus monkeys to mitigate cytokine release syndrome induced by ERY22, surrogate for T-cell redirecting bispecific antibody ERY974 for cancer immunotherapy. Toxicol Appl Pharmacol 379:114657. https://doi.org/10.1016/j.taap.2019.114657

    Article  CAS  Google Scholar 

  23. Neelapu SS, Locke FL, Bartlett NL et al (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531–2544. https://doi.org/10.1056/NEJMoa1707447

    Article  CAS  Google Scholar 

  24. He X, Klasener K, Iype JM, Becker M, Maity PC, Cavallari M, Nielsen PJ, Yang J, Reth M (2018) Continuous signaling of CD79b and CD19 is required for the fitness of Burkitt lymphoma B cells. EMBO J. https://doi.org/10.15252/embj.201797980

    Article  Google Scholar 

  25. Shulzhenko N, Morgun A, Matzinger P (2009) Spontaneous mutation in the Cd79b gene leads to a block in B-lymphocyte development at the C’ (early pre-B) stage. Genes Immun 10:722–726. https://doi.org/10.1038/gene.2009.70

    Article  CAS  Google Scholar 

  26. Kim JH, Kim WS, Ryu K, Kim SJ, Park C (2016) CD79B limits response of diffuse large B cell lymphoma to ibrutinib. Leuk Lymphoma 57:1413–1422. https://doi.org/10.3109/10428194.2015.1113276

    Article  CAS  Google Scholar 

  27. Teachey DT, Rheingold SR, Maude SL et al (2013) Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121:5154–5157. https://doi.org/10.1182/blood-2013-02-485623

    Article  CAS  Google Scholar 

  28. Moore PA, Zhang W, Rainey GJ et al (2011) Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood 117:4542–4551. https://doi.org/10.1182/blood-2010-09-306449

    Article  CAS  Google Scholar 

  29. Zheng B, Fuji RN, Elkins K et al (2009) In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates. Mol Cancer Ther 8:2937–2946. https://doi.org/10.1158/1535-7163.MCT-09-0369

    Article  CAS  Google Scholar 

  30. Klinger M, Zugmaier G, Nagele V et al (2020) Adhesion of T cells to endothelial cells facilitates Blinatumomab-associated neurologic adverse events. Cancer Res 80:91–101. https://doi.org/10.1158/0008-5472.CAN-19-1131

    Article  CAS  Google Scholar 

  31. Staflin K, Zuch de Zafra CL, Schutt LK et al (2020) Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody. JCI Insight. https://doi.org/10.1172/jci.insight.133757

    Article  Google Scholar 

  32. Zuch de Zafra CL, Fajardo F, Zhong W et al (2019) Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell-recruiting antibody optimized for cytotoxicity and cytokine release. Clin Cancer Res 25:3921–3933. https://doi.org/10.1158/1078-0432.CCR-18-2752

    Article  CAS  Google Scholar 

  33. Mandikian D, Takahashi N, Lo AA et al (2018) Relative target affinities of T-cell-dependent bispecific antibodies determine biodistribution in a solid tumor mouse model. Mol Cancer Ther 17:776–785. https://doi.org/10.1158/1535-7163.MCT-17-0657

    Article  CAS  Google Scholar 

  34. Wang Y, Ni H, Zhou S et al (2021) Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol Immunother 70:365–376. https://doi.org/10.1007/s00262-020-02679-5

    Article  CAS  Google Scholar 

  35. Labrijn AF, Janmaat ML, Reichert JM, Parren P (2019) Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov 18:585–608. https://doi.org/10.1038/s41573-019-0028-1

    Article  CAS  Google Scholar 

  36. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012

    Article  CAS  Google Scholar 

  37. Hipp S, Voynov V, Drobits-Handl B, Giragossian C, Trapani F, Nixon AE, Scheer JM, Adam PJ (2020) A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res 26:5258–5268. https://doi.org/10.1158/1078-0432.CCR-20-0926

    Article  CAS  Google Scholar 

  38. Feucht J, Kayser S, Gorodezki D et al (2016) T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget 7:76902–76919. https://doi.org/10.18632/oncotarget.12357

    Article  Google Scholar 

  39. Mimura K, Teh JL, Okayama H et al (2018) PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci 109:43–53. https://doi.org/10.1111/cas.13424

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all scientists in the Innovent CD79b/CD3 project team.

Funding

This study was supported by Innovent Biologics and grants from Suzhou Municipal Science and Technology Bureau (Grant Number SLJ202011), Jiangsu Commission of Health (Grant Number M2020043) and Special Technical Project of Diagnosis and Treatment of Key Clinical Diseases of Suzhou (Grant Number LCZX201813).

Author information

Author notes

  1. Jie Wang, Chen Li, and Kaijie He these authors contributed equally to this article.

Authors and Affiliations

  1. Innovent Biologics (Suzhou) Co., Suzhou, Jiangsu, China

    Jie Wang, Kaijie He, Zhihui Kuang, Jia Lu, Ying Yao, Fufan He, Ninghuan Li, Li Li, Fenggen Fu, Zhihai Wu, Shuaixiang Zhou, Dian Kang, Xuan Qiu, Min Wu, Yang Liu, Xiaochao Cao, Mengqiu Xu, Bingliang Chen & Weiwei Wu

  2. Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China

    Chen Li & Feng Guo

  3. College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China

    Min Wu & Yang Liu

Authors
  1. Jie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaijie He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhihui Kuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fufan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ninghuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fenggen Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhihai Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shuaixiang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dian Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xuan Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Min Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Xiaochao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mengqiu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Bingliang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Weiwei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Feng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JW, CL and KH designed the experiments, wrote and edited the manuscript. ZK performed the in vitro T cell activation, killing and cytokine release assay. JL performed the pre-toxicology study in HSC-NPG mice. YY, MW and YL designed and performed in vivo tumor growth and ex vivo TIL analysis experiments. FH, LL, XC and MX performed the hybridoma screening and antibody selection. NL, FF and SZ performed the antibody generation and engineering. ZW performed and interpreted all protein biophysical analyses. DK and XQ designed and oversaw GLP monkey studies. BC FG and WW conceived the study, assembled and interpreted all data and edited the manuscript.

Corresponding authors

Correspondence to Bingliang Chen, Weiwei Wu or Feng Guo.

Ethics declarations

Conflict of interest

Chen Li and Feng Guo have no potential conflicts of interest to disclose. All other authors are employees of Innovent Biologics. Innovent Biologics has filed patent applications of this work.

Consent for publication

All authors agree to publish this article.

Ethical approval

All mice experiments were performed in accordance with the regulations for care and use of laboratory animals at Innovent Biologics and were approved by the Institutional Animal Care and Use Committee. All monkey experiments were approved by IACUC and performed by WestChina-Frontier PharmaTech, according to the regulations of Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

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 (DOCX 1200 kb)

Rights and permissions

Springer Nature or its licensor 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

Wang, J., Li, C., He, K. et al. Characterization of anti-CD79b/CD3 bispecific antibody, a potential therapy for B cell malignancies. Cancer Immunol Immunother 72, 493–507 (2023). https://doi.org/10.1007/s00262-022-03267-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-022-03267-5

Keywords

Search

Navigation