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A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

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Abbreviations

ABC:

Antibodies bound per cell

APC:

Allophycocyanin

BiTE:

Bispecific T cell engager

bsAb:

Bispecific antibody

CHO:

Chinese hamster ovary

DART® :

Dual-affinity retargeting

LP-DART:

Half-life extended dual-affinity retargeting

NSG:

NOD scid gamma

PDX:

Patient-derived xenograft

PK:

Pharmacokinetic

RLU:

Relative light unit

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Acknowledgements

DART® is a registered trademark of MacroGenics Inc. The authors would like to additionally acknowledge the contributions of the following Pfizer Inc. colleagues to the presented body of work: Alison Betts, Michael Cinque, Magali Guffroy, Tim Nichols, Leslie Obert, Alan Opsahl, and Nicole Streiner.

Author information

Authors and Affiliations

  1. Oncology Research and Development Pfizer Inc., La Jolla, CA, USA

    Timothy S. Fisher, Andrea T. Hooper, Justin Lucas, Allison K. Rohner, Bryan Peano, Mark W. Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Hans-Peter Gerber & Chad May

  2. Oncology Research and Development Pfizer Inc., Pearl River, NY, USA

    Timothy S. Fisher, Andrea T. Hooper, Justin Lucas, Allison K. Rohner, Bryan Peano, Mark W. Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Hans-Peter Gerber & Chad May

  3. BioMedicine Design Pfizer Inc., Cambridge, MA, USA

    Tracey H. Clark, Nahor Haddish-Berhane, Lioudmila Tchistiakova & Adam R. Root

  4. Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA, USA

    Nahor Haddish-Berhane

  5. Maverick Therapeutics, Brisbane, CA, USA

    Hans-Peter Gerber & Chad May

  6. Pfizer Inc., 10777 Science Center Drive, San Diego, CA, 92121, USA

    Timothy S. Fisher

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  1. Timothy S. Fisher
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  2. Andrea T. Hooper
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Contributions

Timothy S. Fisher: writing, editing, experimental design, execution and interpretation of results. Andrea T. Hooper: writing, editing, experimental design and interpretation of results. Justin Lucas: writing, experimental design and execution. Tracey H. Clark: writing, experimental design and execution. Allison K. Rohner: experimental design and execution. Bryan Peano: experimental design and execution. Mark W. Elliott: experimental design and execution. Konstantinos Tsaparikos: experimental design and execution. Hui Wang: editing, experimental design and interpretation of results. Jonathon Golas: experimental design and execution. Maria Gavriil: experimental design and execution. Nahor Haddish-Berhane: experimental design and interpretation of results. Lioudmila Tchistiakova: experimental design and interpretation of results. Hans-Peter Gerber: experimental design and interpretation of results. Adam R. Root: experimental design and interpretation of results. Chad May: writing, editing, experimental design, and interpretation of results.

Corresponding author

Correspondence to Timothy S. Fisher.

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No relevant funding.

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval and ethical standards

All animal experimental procedures complied with the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, 1996) and were approved by the Pfizer Global Research and Development Institutional Animal Care and Use Committee. All human blood samples from healthy donors were collected through the Pfizer Global Occupational Health and Wellness research support program under review of the Institutional Review Board provided with informed consent compliant with guidelines set forth by the International Conference on Harmonization on Good Clinical Practice, as well as local regulatory and legal requirements.

Additional information

Text from this paper was included in a published short abstract for an oral presentation at the 23rd International Molecular Medicine Tri-Conference March 8, 2016, San Francisco, USA.

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Fisher, T.S., Hooper, A.T., Lucas, J. et al. A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice. Cancer Immunol Immunother 67, 247–259 (2018). https://doi.org/10.1007/s00262-017-2081-0

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  • DOI: https://doi.org/10.1007/s00262-017-2081-0

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