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  • Brief Communication
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Immunotherapy

COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia

Leukemia volume 33, pages 805–808 (2019)Cite this article

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Improved survival with the antibody-drug conjugate gemtuzumab ozogamicin (GO) observed in some patients validates CD33 as target for immunotherapy of acute myeloid leukemia (AML) [1]. Still, GO is not effective in many people with AML. There is thus ongoing interest in developing newer, improved CD33-directed therapeutics to overcome GO’s limitations. Since failure of GO-based therapy is at least partially attributable to relatively slow CD33-facilitated intracellular drug delivery and frequent expression of ATP-binding cassette (ABC) transporter proteins mediating multidrug resistance [1], bispecific antibodies that re-direct T-cells toward AML cells have great appeal to accomplish this task. Emerging data with blinatumomab, a CD3/CD19 molecule built in the Bispecific T-cell Engager (BiTE®) format indeed show such antibodies can be highly efficacious against leukemia cells even when multi-agent chemotherapy has failed [2]. After demonstration of broad anti-leukemia activity in preclinical models, a first CD3/CD33 BiTE (AMG 330) has recently entered phase 1 testing [3].

Because of their small size, BiTEs and similar fragment antibodies are efficiently cleared from the circulation with, in the case of blinatumomab, an elimination half-life of approximately 2 h [4]. The resulting requirement for continuous drug administration via infusion pumps offers a logistical challenge and may put a vulnerable patient population at higher risk for infections. To address these limitations, we developed a CD3/CD33-directed bispecific FynomAb (COVA4231) as candidate molecule for the treatment of AML. FynomAbs are generated by fusing Fynomers to antibodies. Fynomers are small (7 kDa), stable, globular binding proteins derived from the human Fyn SH3 domain that can be engineered in the two flexible loops (RT and n-Src loops) to bind to virtually any target with similar affinity and specificity as antibodies. As non-antibody protein scaffold, the Fyn SH3 domain offers attractive features for binding proteins, including ease of production, good stability, lack of cysteine residues, and human origin with high sequence conservation across species. A human Fyn SH3 phage library containing over 85 billion individual clones has been generated to serve as basis for Fynomers. Fynomers can be fused to antibodies at any of the four antibody light- or heavy chain termini to build bi- or multi-specific FynomAbs with drug-like properties [5,6,7].

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Acknowledgements

This research was funded in part through a sponsored research agreement from Covagen (to RBW). RBW is a Leukemia and Lymphoma Society Scholar in Clinical Research.

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  1. These authors contributed equally: Simon Brack, Roland B. Walter.

Authors and Affiliations

  1. Covagen, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Schlieren, Switzerland

    Kristina Klupsch, Vanessa Baeriswyl, Roland Scholz, Joana Dannenberg, Roger Santimaria, David Senn, Elena Kage, Adrian Zumsteg, Isabella Attinger-Toller, Ulrike von der Bey, Susann König-Friedrich, Fanny Dupuy, Wibke Lembke, Clara Albani, Severin Wendelspiess, Lucijana Dinkel, Julian Bertschinger & Simon Brack

  2. Janssen R&D, Spring House, PA, USA

    Dorina Saro & Robert W. Hepler

  3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    George S. Laszlo, Chelsea J. Gudgeon & Roland B. Walter

  4. Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA

    Roland B. Walter

  5. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Roland B. Walter

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  1. Kristina Klupsch
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  22. Simon Brack
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Corresponding authors

Correspondence to Simon Brack or Roland B. Walter.

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Conflict of interest

KK, VB, RS, JD, RS, DS, EK, AZ, IA-T, UvdB, SK-F, FD, WL, CA, SW, LD, JB, and SB are employees of Covagen AG. DS and RWH are employees of Janssen R&D. RBW received laboratory research grants and/or clinical trial support from Actinium Pharmaceuticals, Inc., Amgen Inc., Amphivena Therapeutics, Inc., Aptevo Therapeutics, Inc., Covagen AG, and Seattle Genetics, Inc.; has ownership interests with Amphivena Therapeutics, Inc.; and is (or has been) a consultant to Amphivena Therapeutics, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, Covagen AG, Emergent Biosolutions, Inc. (now Aptevo Therapeutics, Inc.), Pfizer, Inc., and Seattle Genetics, Inc. GSL and CJG declare that they have no conflict of interest.

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Klupsch, K., Baeriswyl, V., Scholz, R. et al. COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia. Leukemia 33, 805–808 (2019). https://doi.org/10.1038/s41375-018-0249-z

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