Abstract 2776: MEDI5752: A novel bispecific antibody that preferentially targets CTLA-4 on PD-1 expressing T-cells

Abstract

Studies have demonstrated that the clinical benefit of PD-1 blockade can be further improved by combination with an αCTLA-4 mAb in some indications. However, this increased activity is commensurate with significant immune related adverse events (irAE's). Therefore, novel approaches are required to uncouple toxicity from anti-tumour efficacy and realise the full potential of this combination. MEDI5752 is a monovalent bispecific human IgG1 monoclonal antibody (mAb) with an engineered fragment crystallisable (Fc) domain to reduce Fc effector function, that specifically binds two clinically validated negative T cell regulators; PD-1 (programmed cell death 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). MEDI5752 has been designed to suppress the PD-1 pathway and provide modulated CTLA-4 inhibition to uncouple CTLA-4 dependent peripheral toxicity from tumour efficacy. PD-1 expression is a defining feature of tumour infiltrating lymphocytes (TILs). We show that MEDI5752 can saturate CTLA-4 on PD-1+ cells at orders of magnitude lower concentrations than required to saturate CTLA-4 on PD-1- cells. Moreover, our data demonstrate that monovalent targeting of CTLA-4 with MEDI5752 is significantly less potent (15 fold) than bivalent targeting with a parental αCTLA-4 mAb in reporter assays. In contrast, the switch to monovalent targeting of PD-1 has limited effect on potency (within 3-fold compared to a parental αPD-1 mAb) in a PD-1/L1 reporter assay. Together these data demonstrate the potential for MEDI5752 to inhibit CTLA-4 on TILs whilst sparing peripheral T cell populations and reducing toxicity. Furthermore, profiling of MEDI5752 in a range of primary T cell activation assays reveals equivalent activity to a combination of parental PD-1 and CTLA-4 antibodies. MEDI5752 is rapidly internalised upon target binding with kinetics similar to the parental αCTLA-4 mAb reflecting the rapid recycling of this receptor. However, in contrast to an αCTLA-4 mAb (or an αPD-1 mAb), MEDI5752, by tethering CTLA-4 to PD-1, leads to the internalisation and subsequent degradation of PD-1. This novel mechanism of action further differentiates MEDI5752 from a combination of mAb's targeting PD-1 and CTLA-4. MEDI5752 is a novel monovalent bispecific which may provide an improved therapeutic index when compared to a combination of bivalent αPD-1 and αCTLA-4 mAb's, and could provide benefit in cancer indications. Citation Format: Simon J. Dovedi, Yariv Mazor, Matthew Elder, Sumati Hasani, Bo Wang, Suzanne Mosely, Desmond Jones, Anna Hansen, Chuning Yang, Yanli Wu, Ikbel Achour, Nick Durham, Gareth Browne, Thomas Murray, James Hair, Michelle Morrow, Godfrey Rainey, Maria Jure Kunkel, John Gooya, Daniel Freeman, Ronald Herbst, Robert Wilkinson. MEDI5752: A novel bispecific antibody that preferentially targets CTLA-4 on PD-1 expressing T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2776.

Enabling the next steps in cancer immunotherapy: from antibody-based bispecifics to multispecifics, with an evolving role for bioconjugation chemistry

“…For instance, PD-1/PD-L1 axis inhibition was shown to improve anti-tumour efficacy by reversing related immune resistance when used in combination with various types of T cell engagers, including αHER2 × αCD3, 162 αCEA × αCD3, 163 αCD33 × αCD3, 164 αTrop-2 × αCD3 and αCEACAM5 × αCD3 BsAbs. 165 Numerous other examples of immunomodulatory antibodies used in combination therapy, not only with BsAbs, have been reported and reviewed, notably by Patel et al 166 Two immunomodulators can also be combined into the same BsAb, generating a dual immunomodulatory BsAb that has the potential to: (1) avoid immune escape by blocking two different inhibitory immune checkpoints (such dual immune checkpoint inhibitory BsAbs include αPD-1 × αCTLA-4, αPD-1 × αTIM-3, and αPD-1 × αLAG3 bispecifics 167–169 ); (2) induce a strong stimulation and expansion of T cells when combining two immunostimulators ( e.g. dual agonistic BsAb αCD137 × αOX40); 170 and (3) induce a synergistic effect when blocking an inhibitory immune checkpoint and activating a stimulatory immune checkpoint – this type of BsAb is sometimes defined as an agonist redirected checkpoint (αPD-1 × αOX40, αCTLA-4 × αOX40).…”

Development of Bispecific Antibody for Cancer Immunotherapy: Focus on T Cell Engaging Antibody

“…MEDI5752 (PD-1×CTLA-4) inhibits the function of CTLA-4 in PD-1 + activated T cells, inducing rapid internalization and degradation of PD-1. Also, MEDI5752 showed enhanced activity compared to that of the combination of PD-1 and CTLA-4 mAb treatment ( 41 42 ). Functional inhibitors targeting other checkpoint molecules, including LAG-3 and TIM-3, are under development ( 43 44 ).…”

Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies

“…For example, MEDI5752 (PD-1 × CTLA-4) is a monovalent BsAb that inhibits PD-1 and CTLA-4 with reduced Fc function and was designed to block CTLA-4-mediated inhibition on PD-1 + T cells. Upon binding to targets, MEDI5752 is rapidly internalized and leads to the subsequent degradation of PD-1, which is not observed with mAbs [ 113 , 114 ]. BsAbs targeting LAG-3, Tim-3, and TIGIT with PD-(L)1 have been developed actively because of better efficacy than combinations in preclinical studies [ 115 ].…”