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Antagonizing the CD47-signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promoted human monocyte-derived dendritic cell-mediated T cell proliferation. In humanized mouse models, AL008 induced internalization of SIRPα and increased expression of CD86 and HLA-DR on human tumor-associated macrophages, confirming that the mechanism of action is retained in vivo. Monotherapy treatment with AL008 significantly reduced tumor growth in humanized mice implanted with human MDA-MB-231 tumor cells. AL008 also significantly potentiated the effects of T cell checkpoint blockade with anti-programmed death ligand-1 in syngeneic tumor models. This dual and specific mechanism of AL008, to our knowledge, provides a novel therapeutic strategy for targeting myeloid cells for immune activation., (Copyright © 2023 by The American Association of Immunologists, Inc.)

The sialic acid-binding immunoglobulin-like lectin (Siglec)-sialic acid immune axis is an evolutionarily conserved immunoregulatory pathway that provides a mechanism for establishing self-recognition and combatting invasive pathogens. Perturbations in the pathway lead to many immune dysregulated diseases, including autoimmunity, neurodegeneration, allergic conditions, and cancer. The purpose of this review is to provide a brief overview of the relationship between Siglecs and sialic acid as they relate to human health and disease, to consider current Siglec-based therapeutics, and to discuss new therapeutic approaches targeting the Siglec-sialic acid immune axis, with a focus on cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules., Patients and Methods: The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels., Results: In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure., Conclusions: Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors., Clinical Trial Number: NCT01362374., Competing Interests: Disclosures All authors report support of the parent study and funding of editorial support from F. Hoffmann-La Roche Ltd. SJI has received research funding from AbbVie, AstraZeneca, Biocartis, Genentech, Merck, OncoPep, and PharmaMar and consulting fees from AbbVie, Genentech, Hengrui, Immunomedics, Mylan, Myriad, PharmaMar, and Puma. JT has received consulting fees from Array BioPharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Roche, Foundation Medicine, Genentech, Genmab, HalioDx, Halozyme, Imugene, Inflection Biosciences, Ipsen, Kura Oncology, Lilly, Merck Sharp & Dohme, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho, and VCN Biosciences. J-CS has received consulting fees from AstraZeneca, Astex, Clovis, GamaMabs, GSK, Lilly, Merus, Mission Therapeutics, Merck Sharp & Dohme, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; is a shareholder of AstraZeneca and Gritstone; and has been a full-time employee of AstraZeneca since September 2017. AC has received consulting fees from Astellas, Bayer, BeiGene, Lilly, Merck Serono, Novartis, Pierre Fabre, Roche, Servier, and Takeda; research funding from amcure, Astellas, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, FibroGen, Genentech, Lilly, MedImmune, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, Servier, Sierra Oncology, and Takeda; speakers bureau fees from Amgen, Bayer, Foundation Medicine, Merck Serono, Roche, and Servier; and grant support from Merck Serono and Roche; he is also an executive board member of ESMO, the Chair of Education of ESMO, the General and Scientific Director of INCLIVA, the associate editor of Annals of Oncology and ESMO Open and the Editor in Chief of Cancer Treatment Reviews. NJV has received consulting fees from Novartis and Pfizer; honoraria from Bayer, Genentech, and Sanofi; and speakers bureau fees from Bayer and Sanofi. MP has received speakers bureau fees from Celgene, EMD Serono, Exelixis, and Pharmacyclics. MH has received consulting fees from AstraZeneca, Bayer, and Pfizer; speakers bureau fees from Aptitude Health, Epics, Genentech, Research to Practice, and Sanofi/Genzyme; and institutional research funding from AstraZeneca, Bayer, Genentech, and Pfizer. GA has received personal research grants from Amgen, Bayer, Bristol-Myers Squibb, Roche, Menarini, Merck Serono, and Servier and institutional honoraria from Bayer, Boehringer Ingelheim, Boston Pharmaceuticals, Genentech, Roche, Novartis, and Servier. DS, PP, and DM were employees of Genentech at the time of study and DM was a shareholder at Genentech. SG, LM, NX, MH, and KL are employees and shareholders at Genentech. JB has received institutional research funding from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, ARMO, Array BioPharma, Arrys, AstraZeneca, Bayer, Bellicum, Boehringer Ingelheim, Blueprint, Bristol-Myers Squibb, Boston Biomedical, Calithera, Celgene, Celldex, CytomX, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Genentech, Gilead, GSK, Harpoon, ImClone, Incyte, Innate, Ipsen, Jacobio, Koltan, LEAP, Lilly, MacroGenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Nektar, Novartis, NovoCare, OncoGenex, OncoMed, Onyx, Pfizer, Pieris, Prelude Oncology, Rgenix, Roche, Sanofi, Sierra, SynDevRex, Taiho, Takeda, Tarveda, TG Therapeutics, Tracon, Tyrogenex, Unum Therapeutics, and Vyriad and institutional consulting fees from Agios, Amgen, Apexigen, Arch Oncology, ARMO, Array BioPharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Five Prime, FORMA, Genentech, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, Kyn, LEAP, Lilly, MacroGenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, OncoGenex, OncoMed, Phoenix Bio, Prelude Therapeutics, Roche, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (translational drug development), TG Therapeutics, Tizona, Tolero, and Torque., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)