The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity

Abstract

Background Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy

“…However, only in patients with functional CD4 T cells, PD-L1/PD-1 blockade achieved reactivation of systemic CD8 immunity. Highly dysfunctional CD4 T cells from non-responder patients recovered their proliferative activities ex vivo by PD-1 and LAG-3 co-blockade [ 21 ]. It has to be mentioned that PD-1/LAG-3 co-blockade is demonstrating significant clinical improvement for the treatment of melanoma, having been approved recently by the FDA [ 43 ].…”

“…It has to be remarked that part of the strong dysfunctionality observed in both CD4 and CD8 T cells is caused by co-expression of multiple immune checkpoint molecules. An example is PD-1 with LAG-3 [ 21 , 29 , 187 ]. LAG-3 expression in CD4 and CD8 T cells together with PD-1 conferred resistance to PD-L1/PD-1 blockade.…”

“…Many tumor types respond to anti-tumor T cells by up-regulating the surface expression of PD-L1, which binds to its receptor PD-1 on the surface of tumor-infiltrating T cells (TILs). PD-L1/PD-1 binding then delivers inhibitory signals leading to T cell inactivation through several mechanisms ( Figure 1 ) [ 17 , 18 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Clinical landscape of LAG-3-targeted therapy

“…CB213 is a half-life extended version delivering simultaneous PD-1 and LAG-3 checkpoint blockade specifically targeted toward highly dysfunctional LAG-3þ PD-1þ double-positive T cells. 26,104 This approach has been designed to deliver safer, more effective therapeutic interventions in patients with cancers resistant or refractory to PD-1 monotherapies. In preclinical testing, CB213 has demonstrated a potent dual checkpoint blockade activity with the ability to revert the dysfunctionality of patientderived T cells.…”

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

“…CB213 Humabody ® , a PD-1xLAG-3 antagonist developed by Crescendo Biologics Ltd., have recently entered a partnership with Cancer Research UK for its clinical development into a future phase I clinical trial ([ 110 ]). This bispecific molecule binds and blocks with high affinity PD1 and LAG-3 on PD-1+LAG-3+ T cells, induces ex vivo T cell proliferation of dysfunctional T cells from NSCLC patients, with superior activity than anti-PD-1 alone and suppress tumor growth in vivo [ 111 ].…”