Targeting CD47 and PD-L1 Immune Checkpoints with Bispecific Antibodies

Diplôme Thèse Targeting CD47 and PD-L1 Immune Checkpoints with Bispecific Antibodies eng 2022-06-29 author Penarrieta Elise 0000-0002-6161-4909 699944 director Masternak Krzysztof 503788 director Martinou Jean-Claude 27293 10.13097/archive-ouverte/unige:163271 urn:nbn:ch:unige-1632715 Sc. Vie 167 Cancer cells can evade immune system surveillance by creating an immunosuppressive microenvironment and by expressing inhibitory molecules, such as PD-L1 and CD47. The latter is an innate immune checkpoint and a marker of “self” expressed by virtually all cells. Upon its interaction with SIRPα, CD47 protects cells from destruction by innate immune phagocytes, a mechanism that is hijacked by many cancers. In pre-clinical studies, anti-CD47 monoclonal antibodies (mAbs) promoted tumor elimination by increasing phagocytosis of tumor cells and by enhancing antigen cross presentation, thus providing a strong rationale for CD47 targeting in the clinic. A large number of anti-CD47 mAbs and SIRPα-Fc fusion proteins are now being tested in clinical trials. Notwithstanding, monospecific CD47 targeting suffers from important limitations, such as poor pharmacokinetics and hematotoxicity related to the ubiquitous expression of CD47, including on platelets and on red blood cells (the so called “CD47 antigen sink”). CD47-targeting with bispecific antibodies represents an alternative and safer approach, allowing to mitigate the “antigen sink” issues, since CD47 targeting can be restricted to defined cell populations. In my PhD thesis work, I investigated the anti-tumor efficacy, the pharmacokinetics, and the mechanism of action of CD47|PD-L1 bsAbs in the context of different Fc portions (either active or silenced Fc). As expected, the bsAbs efficiently blocked the PD-1/PD-L1 and CD47/SIRPα interactions on double positive cells and showed minimal binding to PD-L1 negative cells, such as red blood cells. In vivo, these bsAbs showed a modest effect on tumor growth in the MC38 syngeneic model, but no difference in anti-tumor efficacy was apparent when comparing a bsAb with an active Fc with its silenced Fc counterpart. However, Fc silencing significantly improved the pharmacokinetics of the CD47|PD-L1 bsAb, confirming the notion that FcγR binding may contribute to antibody elimination, probably by exaggerating the TMDD (target-mediated drug disposition) rate. Finally, I also performed an analysis of the tumor microenvironment and showed that the bsAb treatment enhanced both the innate and the adaptive immune responses, as demonstrated by an increase in M1-like macrophages and CD8+ T cell infiltration. CD47 PD-L1 Bispecific antibody Immune checkpoint Cancer immunotherapy Dewey 570 30 Section de biologie 16 false b2ff26b9-ee3e-448a-9303-a7927e4a32af Thesis Public 202209_Thesis_EP.pdf 8424315 application/pdf 767cc366-88e0-409e-b06d-a8228e3c3402 Imprimatur Public Imprimatur EP.pdf 62899 application/pdf 344d455d-3c48-4ff0-814d-a31f5f8a0ec9 Publication mode Private Mode de publication EP.pdf 97504 application/pdf c9163d48-02ac-4b37-9b72-1356930e91ea Agreement Private Contrat_diffusion_these_vDocuSign.d.pdf 495748 application/pdf openAccess Faculté des sciences / Section de biologie

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Targeting CD47 and PD-L1 Immune Checkpoints with Bispecific Antibodies	2022	496	516
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Penarrieta, Elise

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