Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies

Abstract

Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.

Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab

“…It is also somewhat surprising that all these PD-L1 blocking antibodies bind PD-L1 on the flat front beta-sheet as generally targeting a relatively flat protein surface is very challenging. When compared with other immune checkpoint blocking antibodies, we have found that CTLA-4 blocking antibodies such as ipilimumab (PDB:5TRU) and tremelimumab (PDB:5GGV) similarly target the front surface of IgV domain of CTLA-4, while PD-1 blocking antibodies such as pembrolizumab (PDB:5GGS) and nivolumab (PDB:5GGR) mainly bind PD-1 on the connecting loops of the front beta-sheet [ 18 , 22 – 24 ]. It is unclear if the differences in the epitopes of these receptors are due to the differences in antibody screening processes or due to differences in the geometry and electrostatic properties of the IgV domains of these receptors.…”

Characterization of CTLA4 Trafficking and Implications for Its Function

“…The therapeutic ligands typically bind CTLA4 with higher affinities than natural ligands, which enables their exploitative binding. For example, Ipilimumab (k D ¼ 18.2 nM) and Tremelimumab (k D ¼ 5.89 nM) bind CTLA4 with higher affinity compared to natural ligands (k D,CD86 ¼ 2.6 mM, k D,CD80 ¼ 0.2 mM) (39,40). A mapping between affinities (off rates) to the uptake kinetics of physiological ligands in our model should be made with caution because of the factors that cannot be inferred experimentally and the impact of multivalent avidity affecting ligand binding.…”

Immunotherapy in Non-Small Cell Lung Cancer: Shifting Prognostic Paradigms

“…Based on the experience from the melanoma cohort and the CheckMate-data in lung, it does appear that combination therapy can provide a broader, more durable response [ 44 ]. Should the final MYSTIC data not meet the OS end-point, doubt will likely be cast on the efficacy of tremelimumab, an IgG2 antibody with slightly different binding properties to its IgG1 counterpart, ipilimumab, rather than the potential of combination therapy [ 45 ].…”