Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40-60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3's effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15-25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.

Antibody therapies for the treatment of acute myeloid leukemia: exploring current and emerging therapeutic targets.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

COVID-19 and human-nature relationships: Vermonters' activities in nature and associated nonmaterial values during the pandemic.

The COVID-19 pandemic has rapidly modified Earth's social-ecological systems in many ways; here we study its impacts on human-nature interactions. We conducted an online survey focused on peoples' relationships with the non-human world during the pandemic and received valid responses from 3,204 adult residents of the state of Vermont (U.S.A.). We analyzed reported changes in outdoor activities and the values associated with human-nature relationships across geographic areas and demographic characteristics. We find that participation increased on average for some activities (foraging, gardening, hiking, jogging, photography and other art, relaxing alone, walking, and watching wildlife), and decreased for others (camping, relaxing with others). The values respondents ranked as more important during the pandemic factored into two groups, which we label as "Nurture and Recreation values" and "Inspiration and Nourishment values." Using multinomial logistic regression, we found that respondents' preferences for changes in activity engagement and value factors are statistically associated with some demographic characteristics, including geography, gender, income, and employment status during the pandemic. Our results suggest that nature may play an important role in coping during times of crisis, but that the specific interactions and associated values that people perceive as most important may vary between populations. Our findings emphasize for both emergency and natural resources planning the importance of understanding variation in how and why people interact with and benefit from nature during crises.