Building a preclinical case for intratumoral DNA-based immunomodulatory antibody therapy

DNA-based monoclonal antibody (mAb) gene transfer presents an appealing alternative to conventional recombinant mAb therapy. This approach aims to administer the mAb-encoding nucleotides rather than the mAb protein, enabling the site of delivery to produce the drug for a prolonged period of time1. We recently reported preclinical proof of concept for intramuscular mAb gene transfer, demonstrating mAb expression for at least nine months at therapeutically effective plasma concentrations2. In the current study, we explored the tumor as site of delivery for two DNA-based immunomodulatory mAbs, referred to as ‘pAb1’ and ‘pAb2’. We hypothesize that local expression of these mAbs can induce anti-tumor responses, while avoiding prolonged systemic exposure and the associated risk of toxicity.

We previously selected electroporation as the transfection method of choice for intratumoral (IT) plasmid DNA (pDNA) administration3. C57BL/6 mice bearing a subcutaneous MC38 tumor received six IT electroporations of pAb1, pAb2, pAb1 + pAb2, or an empty plasmid pNull (six mice per group) over the course of ten days. Compared to a group of untreated mice, electroporation by itself resulted in significant tumor growth delay, irrespective of the pDNA. Compared to pNull, expression of the immunomodulatory mAbs further enhanced the anti-tumor response and survival (number of mice with complete tumor regressions in pAb1 group = 1; pAb2 = 2; pAb1 + pAb2 = 2; pNull = 0; untreated = 0). mAb1 and mAb2 plasma concentrations peaked 2-3 weeks after the first IT pDNA delivery (median [range], 151 ng/ml [42 – 1035 ng/ml]), and dropped below 50 ng/ml [0 – 43 ng/ml] 4-5 weeks later. Compared to intramuscular pDNA electrotransfer, IT expression led to 20-fold lower mAb plasma titers and appeared shorter in duration.

In summary, IT mAb gene transfer led to significant tumor regressions and low, transient mAb concentrations in plasma. These data demonstrate the potential of this approach towards maximizing efficacy and minimizing systemic toxicity of immunomodulatory mAbs.

1. Hollevoet K, Declerck PJ. State of play and clinical prospects of antibody gene transfer. J Transl Med (2017) 15:131-150.
2. Hollevoet K et al. Prolonged in vivo expression and anti-tumor response of DNA-based anti-HER2 antibodies, under review.
3. Jacobs L et al. Electroporation outperforms in vivo-jetPEI for intratumoral DNA-based reporter gene transfer. 2nd World Congress on Electroporation, Norfolk, US, Sept 19-22, 2017.

Authors

Liesl Jacobs (1)
Nick Geukens (2)
Elien De Smidt (2)
Paul Declerck (1)
Kevin Hollevoet (1)

Organisations

KU Leuven - University of Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, O&N II Herestraat 49 box 820, Leuven, Belgium (1)
KU Leuven - University of Leuven, PharmAbs - the KU Leuven Antibody Center, O&N II Herestraat 49 box 820, Leuven, Belgium (2)

Presenting author

Liesl Jacobs, PhD student, KU Leuven
liesl.jacobs@kuleuven.be
Contact us now

Flanders.bio Strategic Partners