The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better

Abstract

The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART’s efficacy has not been carefully investigated. In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5.7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses. Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective. We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high Kon and Koff) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion. We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

“…This would allow for CAR T cell expansion for improved efficacy without toxicity. A recent review has further suggested that lower CAR affinity correlates with a more positive clinical response [84]. The improved fitness of CAR T cells having lower affinities also has been documented previously [73–76].…”

A method for rapid nanobody screening with no bias of the library diversity

“…To demonstrate the diversities of isolated nanobodies, we further probed if the binding epitopes of different nanobodies on Pfu DNA polymerase overlapped with each other via NMR spectroscopy. For each of the isolated Pfu nanobodies, both 15 N labeled and unlabeled samples were expressed and purified. The 15 N- 1 H HSQC spectrum of each isolated nanobody was first measured in the presence and absence of Pfu DNA polymerase.…”

“…By contrast, several recent studies highlighted the importance of the diversity of antibodies. Low-or moderate-affinity rather than high-affinity antibodies deliver greater activity, even when they share overlapping binding epitopes with the high-affinity antibody [13][14][15] . Thus, the development of new methods for antibody discoveries is needed to overcome the problem of the convergence of the library.…”

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

“…To date, no guidelines are available for developing optimal CAR affinity for a given antigen. However, relevant retrospective studies evaluating clinical and preclinical data on the affinity of CAR for solid cancer cells have shown that an intermediate affinity (K D of ~20-100 nM) of CAR-scFv has better clinical efficiency than a higher affinity [50,61]. However, this finding does not apply to the Food and Drug Administration (FDA)-approved 19CAR binding domain.…”