Is SARS-CoV-2 Neutralized More Effectively by IgM and IgA than IgG Having the Same Fab Region?

Recently, recombinant monoclonal antibodies (mAbs) of three Ig isotypes (IgG, IgA, and IgM) sharing the same anti-spike protein Fab region were developed; we evaluated their neutralizing abilities using a pseudo-typed lentivirus coated with the SARS-CoV-2 spike protein and ACE2-transfected cat Crandell–Rees feline kidney cells as the host cell line. Although each of the anti-SARS-CoV-2 mAbs was able to neutralize the spike-coated lentiviruses, IgM and IgA neutralized the viral particles at 225-fold and 125-fold lower concentrations, respectively, than that of IgG. Our finding that the neutralization ability of Igs with the same Fab domain was dramatically higher for IgM and IgA than IgG mAbs suggests a strategy for developing effective and affordable antibody therapies for COVID-19. The efficient neutralization conferred by IgM and IgA mAbs can be explained by their capacity to bind multiple virions. While several IgG mAbs have been approved as therapeutics by the FDA, there are currently no IgM or IgA mAbs available. We suggest that mAbs with multiple antigen-binding sites such as IgM and IgA could be developed as the new generation of therapy.

1242. Safety and Immunogenicity of Novel 24-Valent Pneumococcal Vaccine in Healthy Adults

Background Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vaccines over the past 20 years. Serotype replacement, limited efficacy for certain vaccine serotypes, and the incomplete coverage of disease in the elderly perpetuate the problem. Novel vaccines with broader serotype coverage are needed. To this end, a novel 24-valent pneumococcal vaccine, ASP3772, was developed based on a multiple antigen-presenting system (MAPS) platform. This platform takes advantage of the high affinity, noncovalent binding between biotin and rhizavidin to create a complex of 24 pneumococcal polysaccharides and a fusion of two pneumococcal proteins. Methods Healthy adults aged 18-64 years were randomized into this active-controlled, observer-blinded, dose-escalation study to evaluate the safety, tolerability, and immunogenicity of ASP3772 at three dose levels compared to Prevnar13 (PCV13) (target 30 per dose group). The primary endpoints were safety and reactogenicity. Immunogenicity was evaluated secondarily by measuring serotype-specific immunoglobulin G (IgG) and opsonophagocytic activity (OPA). Results Ninety-three subjects received ASP3772 at 1 of 3 doses and 33 received PCV13. Safety and reactogenicity were similar between the ASP3772 and PCV13 arms. Most frequently reported local reactions were tenderness and pain after injection occurring within the first 2 days. Most frequent systemic reactions were fatigue, headache, and myalgia, without a clear dose response. Treatment-emergent adverse events were few and most were mild to moderate in severity. No clinically relevant abnormalities were observed in vital signs, ECGs, and laboratory parameters. Robust IgG and OPA responses were observed for serotypes shared with PCV13, as well as serotypes unique to ASP3772. Conclusion ASP3772 vaccine was safe, well tolerated in adults aged 18-64 years, and exhibited robust immunogenicity that extended beyond serotypes shared with PCV13. Disclosures Gurunadh Chichili, PhD, Astellas Pharma Inc (Employee) Ronald Smulders, MD, PhD, Astellas Pharma Inc (Employee) Vicki Santos, n/a, Astellas Pharma Inc (Employee) Beth Cywin, n/a, Astellas Pharma Inc (Employee) Laura Kovanda, n/a, Astellas Pharma Inc (Employee) Frank J. Malinoski, MD, PhD, Affinivax Inc (Employee) Shite Sebastian, PhD, Affinivax Inc (Employee) George R. Siber, MD, Affinivax Inc (Consultant, Employee, Shareholder) Rick Malley, MD, Affinivax Inc (Board Member, Consultant, Employee)

Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.

T Cells Modified with CD70 as an Alternative Cellular Vaccine for Antitumor Immunity

PurposeSuccessful tumor eradication primarily depends on generation and maintenance of a large population of tumor-reactive CD8 T cells. Dendritic cells (DCs) are well-known potent antigen-presenting cells and have applied to clinics as potent antitumor therapeutic agents. However, high cost and difficulty in obtaining sufficient amounts for clinical use are the crucial drawbacks of DC-based vaccines. Here, we aimed to develop T cell–based vaccine capable of eliciting potent antitumor therapeutic effects by providing effective costimulatory signals.Materials and MethodsAntigenic peptide-loaded T cells transfected with retrovirus encoding costimulatory ligands CD70, CD80, OX40L, or 4-1BBL were assessed for antigen-specific CD8 T-cell responses and evaluated antitumor effects along with immunization of a mixture of synthetic peptides, poly-IC and anti-CD40 antibodies (TriVax).ResultsT cells expressing CD70 (CD70-T) exhibited similar level of stimulatory functionality and therapeutic efficacy as DCs. Moreover, CD70-T prime followed by TriVax booster heterologous vaccination elicited therapeutic antitumor effect against B16 melanoma where mediated by CD8 T cells but not CD4 T cells or natural killer cells. The combination with programmed death-ligand 1 blockade led to potent therapeutic efficacy which exhibited increased tumor-infiltrating CD8 T cells. CD70-T pulsed with multi-antigenic peptide generated multiple antigen-specific polyvalent CD8 T cells that were capable of inhibiting tumor growth effectively. Moreover, CD70-T vaccination resulted in higher expansion and migration of adoptively transferred T cells into tumor sites and elicits enhanced therapeutic effects with peptide-based booster immu-nization.ConclusionThese results imply that T cells endowed with CD70 enable the design of effective vaccination strategies against solid cancer, which may overcome current limitations of DC-based vaccines.

Tolerogenic Nanoparticles Impacting B and T Lymphocyte Responses Delay Autoimmune Arthritis in K/BxN Mice

Current treatments for unwanted antibody responses largely rely on immunosuppressive drugs compromising overall immunity. New approaches to achieve antigen-specific tolerance are desirable to avoid unwanted side effects. Several nanoparticle-based approaches designed to tolerize the B or T cell arms of the humoral immune response have shown promise for induction of antigen-specific tolerance, raising the possibility that they could work synergistically if combined. Earlier we showed that Siglec-engaging tolerance-inducing antigenic liposomes (STALs) that display both an antigen (Ag) and glycan ligands of the inhibitory co-receptor CD22 (CD22L) lead to robust antigen-specific B cell tolerance to protein antigens in naïve mice. In another approach, administration of free Ag with poly(lactic co-glycolic acid)-rapamycin nanoparticles (PLGA-R) induced robust antigen-specific tolerance through production of regulatory T cells. Here we illustrate that co-administration of STALs together with PLGA-R to naïve mice induced more robust tolerance to multiple antigen challenges than either nanoparticle alone. Moreover, in K/BxN mice that develop spontaneous autoimmune arthritis to the self-antigen glucose-6-phosphate-isomerase (GPI), co-delivery of GPI-LP-CD22L and PLGA-R delayed onset of disease, and in some mice prevented the disease indefinitely. The results show synergy between B cell-tolerizing STALs and T cell-tolerizing PLGA-R and the potential to induce tolerance in early stage autoimmune disease.

Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy.

16 Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigated against mesothelin-expressing cancer cells with inducible or constitutive PDL1 over expression. In vitro, cytotoxicity upon single and multiple antigen stimulation and proliferation, inhibitory receptor expression (PD1, TIM3 LAG3) were tested. In vivo, tumor burden regression kinetics and median survival were determined in an orthotopic model of pleural mesothelioma. Results: Following single antigen stimulation, both CAR T cells exhibited equivalent cytotoxicity. Following multiple antigen stimulations (antigen stress test), M28z PD1DNR CARs showed sustained and relatively higher cytotoxicity and proliferation compared to M28z CAR T cells, even when combined with anti-PD1 agent. PD1, TIM3 and LAG3 expression upregulation was noticed in both CAR T cells. CAR T cell therapy combined with extrinsic PD1 blockade or intrinsic PD1 DNR demonstrated enhanced and sustained tumor regression and prolonged survival (median survival 66 and 60 days) compared to CAR T cell therapy alone (27.5 days). In mouse model with constitutive PDL1 overexpressing cancer, similar trend is observed (74, 69 versus 28 days). Conclusions: A single dose of M28z CAR T cells with cell-intrinsic PD1DNR demonstrated equal anti-tumor efficacy compared to multiple doses of extrinsic anti-PD1 agent administration in models with inducible and constitutive high-PDL1 expressing cancer with no on-target, off-tumor toxicity with either strategy. This data provides the rationale for our ongoing phase II trial of combination therapy with M28z CAR T cells and anti-PD1 agent, and upcoming M28zPD1DNR CAR T cell trial in 2020.

A Comprehensive review on Dendrimers in current advanced Drug delivery

In this particular review, it is been noted that Dendrimers are novel three-dimensional globular nano-polymeric structure; having multiple functional groups on the surface enhances their function. Synonymous terms for dendrimer include arborols and cascade molecules. The importance of dendrimers in a large variety of fields has been detected, where the various types of dendrimers helps in various fields of drug delivery with the different types of dendrimers with the generation. Hence the dendrimer gains more attention from researchers among various nano-materials. Convenient synthesis of the structure makes them as a good nano-material for drug delivery. In recent, dendrimers showed their activity in different drug delivery systems having properties like cancer targeting, anti-bacterial, ocular drug delivery, etc.. The future direction about the dendrimers are been discussed. The present review is focused on types of dendrimers like Polypropylene Imine dendrimer (PPI), Poly(amidoamine) dendrimers (PAMAM), Poly-l-lysine dendrimers, Type of Frechet’s dendrimer, Core-shell tecto dendrimers, Chiral dendrimers, Liquid crystalline dendrimers, Peptide dendrimers, Multiple antigen peptide dendrimers, Glyco-dendrimers, Hybrid dendrimers, Polyester dendrimers in which among these type of dendrimers, the Polypropylene Imine dendrimer (PPI) and Poly(amidoamine) dendrimers are found to be good carriers for various targeting site, Dendrimers are synthesized through various methods like Divergent method, Convergent method, Hyper cores and branched monomer growth method, Double exponential growth method, Click chemistry method, recent advances in dendrimers are used in the Anti-cancer delivery, Anti-bacterial delivery, oral route delivery, pulmonary drug delivery, transdermal drug delivery, ocular delivery, and targeted drug delivery the safety aspects, and future strategies are also been discussed in the below article.