CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies

Abstract

Despite promising clinical activity, T-cell-engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug. We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug. CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell-binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. , CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD. CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). .

Advances in cellular and humoral immunotherapy – implications for the treatment of poor risk childhood, adolescent, and young adult B‐cell non‐Hodgkin lymphoma

“…A multicentre phase II study of blinatumomab for relapsed/refractory DLBCL found that stepwise dose escalation was necessary to avoid neurological side effects and the ORR was 43% (Viardot et al , ). New bispecific antibody constructs are in clinical trials (Bacac et al , ). Numerous bispecific antibodies that direct T or NK cells to tumour antigens are undergoing preclinical and clinical evaluation (Felices et al , ; Velasquez et al , ).…”

Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies

“…PK/PD modeling can be used to determine the optimal affinity range provided when information about the antigen kinetics, dose range, and human PK is available . The avidity of the antibody to its receptor can also be leveraged to improve potency …”

“…45,46 The avidity of the antibody to its receptor can also be leveraged to improve potency. 47,48 Enhancing the affinity of an antibody for its target must be balanced with potential increases in nonspecific binding to various tissues, which may counterbalance expected improvements in PK/PD. 49 Wu et al 49 applied a directed evolution approach to improve both the association rate (k on ) and dissociation rate (k off ) of palivizumab to the RSV F protein and found that raising the affinity by increasing k on improved virus neutralization for the IgG form of the mAb.…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…BsAbs targeting new antigen specificities may help tackle relapses related to the loss of the target antigen recognition [87] and further expand their application to acute myeloid leukemia (AML) [88 & ] and multiple myeloma [89], with results from phase I studies being awaited with interest [90]. Recent advances in molecular design and genetic engineering facilitated a next generation of optimized antibodies [91] in which a higher avidity and potency may overcome antigen internalization by leukemia cells [92].…”