’Roids without rage via B-cell–targeted ADC?

In this issue of Blood, Chang et al report the preclinical activity and proposed mechanisms of action of a novel CD19-targeting antibody-drug conjugate with a glucocorticoid receptor modulator payload for the treatment of B–cell malignancies.¹ 

Immune-based therapies have substantially changed the cancer treatment landscape over the past decade. Monoclonal antibodies (mAbs) target tumor-specific cell surface proteins, which can engage the immune system to elicit antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADPC), and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) link mAbs to target a tumor cell and deliver a cytotoxic “payload.”² Bispecific T-cell engagers (BiTEs) bind receptors on tumor cells and T cells, engaging them to mediate cell killing. Chimeric antigen receptor (CAR) T-cell (CAR-T) and CAR–natural killer (NK) therapy engineers T cells or NK cells to specifically target cell surface proteins and kill the tumor cells on which they are expressed. B-cell malignancies have certainly benefitted from this boom. There are several US Food and Drug Administration–approved immune-based products, and many more in clinical development include monoclonal antibodies (eg, rituximab), BiTEs (eg, blinatumomab), and CAR-T (eg, tisagenlecleucel).³ ADCs for B-cell malignancies are also ever increasing, covering a spectrum of targets and payloads (see figure).^2,3 

Chang et al took a similar yet distinct path in developing the ADC ABBV-319. Here, similar to several existing products, they target the pan–B-cell marker, CD19, with an afucosylated mAb (Af. CD19 mAb). Given its expression on a broad range of B-cell malignancies from mature lymphomas to acute leukemias, CD19 is an attractive and often used target for immune-based therapies. They most significantly deviate from other ADCs in the therapeutic payload. Although most existing ADCs use payloads that replicates the effects of genotoxic or microtubule poisoning chemotherapies, ABBV-319 leverages the fact that, in addition to shared expression of CD19, another feature common across most B-cell malignancies is sensitivity to glucocorticoids. The therapeutic payload of ABBV-319 is a glucocorticoid receptor modulator (GRM) agonist, designed to engage and activate the endogenous glucocorticoid receptor (eGR). The authors conducted a panel of in vitro and in vivo experiments testing the efficacy of ABBV-319 in B-cell malignancies, finding that treatment with ABBV-319 resulted in potent cell growth inhibition across a spectrum of human cell lines, including aggressive B-cell lymphoma and leukemia subsets.

The authors also explored the mechanisms of response, including those related to the GRM, but also those attributable to the mAb itself. Rigorous investigations demonstrate that upon mAb CD19 binding, internalization, and activation of the GRM payload, the eGR is engaged, activated, and enforces a gene expression program consistent with growth arrest and apoptosis. In addition to the expected effects of the GRM payload, the authors explored the possibility that the mAb itself might contribute to the anti-cancer effects. Further investigations revealed that treatment with the Af. CD19 mAb, even without the linked payload, exerted antiproliferative effects via inhibited activation of B-cell receptor–mediated signaling pathways. Last, the authors postulated that like therapeutic mAbs, the Af. CD19 mAb may result in cell killing via immune cell engagement. They found that naked Af. CD19 mAb and ABBV-319 can engage both ADPC and ADCC (but not CDC). The afucosylation of the CD19 mAb, which was postulated to enhance the Fc-mediated effector function of the mAb was, as expected, associated with more robust ADCC compared with its fucosylated counterpart. Thus, for this ADC, efficacy can be ascribed to both the payload and its antibody carrier.

With several B-cell directed immune-based therapies already clinically available and more in the pipeline, is ABBV-319 cause for excitement? Perhaps the most appealing aspect is the tactic to target glucocorticoid effects. Oncologists specializing in the care of patients with hematologic malignancies have a love/hate relationship with glucocorticoids, such as dexamethasone and prednisone. On the one hand, they are a cornerstone of therapy for most lymphoid malignancies given their potent efficacy. However, although likely necessary for cure, systemic glucocorticoids are associated with several unique and difficult to manage toxicities largely due to effects beyond those exerted on malignant and normal lymphocytes. Frequent “off-target” complications include hypertension, hyperglycemia, increased appetite, weight gain with fat redistribution, skin changes, myopathy, and bone toxicities, including osteonecrosis and fractures.^4,5 Glucocorticoids are also notoriously associated with profound effects on mood and behavior, including mood lability, depression, aggression, sleep disturbance, and agitation.^4-7 In short, steroids take a heavy toll on patient health and quality of life for both patients and their caregivers. Thus, if ABBV-319 can result in the same or even greater efficacy and simultaneously cause less toxicity compared with standard systemic glucocorticoids, it could have a substantial impact on therapeutic approach.

However, much is left to learn about ABBV-319. First, although many of the disease models explored by Chang et al were responsive to ABBV-319, several were not, and this distinction was not dependent on either the level of CD19 or glucocorticoid receptor expression. Therefore, additional explorations must define mechanisms of resistance. Furthermore, although this article provided an excellent view of the efficacy and mechanisms of action of ABBV-319, no data were provided regarding the toxicity profile, including if and how significantly steroid-associated toxicities are reduced. This is important, because while targeted, other ADCs are known to have off-target toxicities, such as the well-characterized liver toxicity of inotuzumoab ozogamicin.^8,9 Undoubtedly, the ongoing clinical trial of ABBV-319 (NCT05512390) will provide these critical data. Last, although this therapy should be effective against any CD19-expressing cancer, including bone marrow–infiltrating leukemias and lymphomas, the in vivo modeling done here was restricted to subcutaneous tumor growth inhibition. To fully understand the in vivo efficacy, the treatment of marrow-engrafted models is needed as there could be marrow microenvironmental mediators of resistance yet to be identified.

With a rigorous set of in vitro and in vivo experiments, Chang et al demonstrate the efficacy and mechanisms of action of a first-in class CD19-targeting ADC. Although more work remains to determine if it warrants a place in therapy, ABBV-319 holds the promise of mitigating some of the most problematic toxicities of therapy for B-cell malignancies.

Conflict-of-interest disclosure: R.E.R.’s spouse is an employee of AbbVie Pharmaceuticals.