Combination Of Antibodies Research Articles

Avutometinib plus cetuximab after chemotherapy in patients with KRAS -mutated metastatic colorectal cancer: Results of phase 1 dose escalation.

199 Background: Anti-EGFR antibodies like cetuximab are ineffective in KRAS mutated (mt) colorectal cancer (CRC) due to constitutive activation of downstream pathways. Avutometinib is a first in class, oral, novel, dual RAF/MEK inhibitor. In patient-derived xenograft models of KRAS mt CRC, the combination of an anti-EGFR antibody with avutometinib conferred stronger tumor growth inhibition than either agent alone. We present results from the dose escalation phase (1b) of an ongoing phase 1b/2 trial evaluating the combination avutometinib plus cetuximab in KRAS mt metastatic (m) CRC. Methods: This is a single-center, open-label, phase 1b/2 study evaluating the safety and combined tolerability of avutometinib and cetuximab. Patients received avutometinib 2.4mg (at DL0) or 3.2mg (at DL1) orally twice a week for 3 weeks out of a 4-week cycle + cetuximab 500mg/m 2 intravenously q2week. Patients with disease progression on, or intolerance to 5-FU, oxaliplatin, and irinotecan, and measurable disease per RECIST v1.1 were enrolled. The primary endpoint for phase 1b was to establish the maximum tolerated dose (MTD) and hence determine the recommended phase 2 dose (RP2D). Dose limiting toxicity (DLT) period was 28 days. A 3+3 dose escalation design was used with dose level (DLs) 0 (2.4mg avutometinib) as the starting level and one dose escalation to DL+1 (3.2mg avutometinib). Results: We report safety results of phase 1b. 10 patients, 7 at DL0 and 3 at DL+1, were enrolled. Median age was 52.5 yrs (range 41 – 75). Any grade (G) treatment related adverse events (TRAEs) were seen in all 10 patients. Most common TRAEs were acneiform rash (100%), chills (30%), diarrhea (30%), and fatigue (30%). G3 TRAEs at DL0 were seen in 4/7 (57.1%) patients and at DL+1 in 2/3 (66.7%) patients. No G4 TRAEs were seen. G3 TRAEs seen at DL0 are noted in the table. One patient from the initial three enrolled was not evaluable due to underdosing. Another patient was later found to not meet eligibility criteria, but they did clear the DLT period. Hence, 6/7 patients at DL0 were evaluated for AE assessment, of which 1 had a DLT. 3 additional patients were enrolled in DL+1. 2/3 patients in DL+1 had grade 3 toxicities (both DLTs) of rash. Hence DL0 was established as the MTD/RP2D. Conclusions: This is the first trial evaluating the combination avutometinib plus cetuximab in KRAS mt mCRC. RP2D for avutometinib was established at 2.4mg orally twice a week for 3 weeks out of a 4-week cycle when used in combination with q2week 500mg/m 2 cetuximab for KRAS mt mCRC. Enrollment continues currently for the dose expansion phase for efficacy assessment. Clinical trial information: NCT05200442 . G3 TRAEs at DL0 attributed to both drugs unless specified. G3 TRAE # of patients Acneiform rash 3/7 (42.9%) Hand-Foot syndrome 1/7 (14.3%) Extremity edema 1/7 (14.3%) Cellulitis 1/7 (14.3%) Sepsis 1/7 (14.3%) Anemia 1/7 (14.3%) Creatine phosphokinase elevation 1/7 (14.3% – avutometinib only)

Design of a humanized CD40 agonist antibody with specific properties using AlphaFold2 and development of an anti-PD-L1/CD40 bispecific antibody for cancer immunotherapy.

Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Assisted by Alphafold2(AlphaFold-Multimer), we developed a humanized CD40 agonistic antibody that exhibits activation only in the presence of cross-linking. It also demonstrates that the current AlphaFold2(AlphaFold2-Multimer) can predict antibody-antigen complexes. Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E). Building upon this, we created a novel bispecific antibody (anti-PD-L1/CD40 bispecific antibody, referred to as "BA4415") designed to activate CD40 signaling specifically in the context of PD-L1 while simultaneously blocking PD-1/PD-L1 signaling. Results from functional evaluations using effector cells revealed the superior biological activity of BA4415 compared to the combination of each monoclonal antibody. BA4415 demonstrated the ability to enhance T-cell cytokine release in vitro assays, exhibiting superior functional attributes compared to the anti-PD-L1 antibody. Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors.

Effectiveness, safety, and impact on multiple sclerosis course of anti-CGRP monoclonal antibodies.

Migraine affects up to 40% of people with multiple sclerosis (PwMS). This study aimed to evaluate the effectiveness and safety of the combination of antibodies (mAbs) against CGRP (anti-CGRP mAbs) with disease-modifying treatments (DMTs) for MS (mAb and non-mAbs) and their impact on MS disease course. This retrospective, multicentric study included PwMS from 14 MS Centers, treated with an anti-CGRP mAb and a stable treatment with DMTs. MS outcome measures included clinical relapses, EDSS score, and MRI activity from the year before starting anti-CGRP mAbs at the time of initiation (baseline) and last follow-up. Migraine outcomes included reductions in Monthly Headache Days (MHDs) and analgesic use. Adverse events (AEs) were recorded. Twenty-five patients were included (mean age of 39.4±9.7years). Nine PwMS (36.0%) were treated with non-mAb DMTs and 16 (64.0%) with mAb DMTs. During the concurrent treatment, six patients (24.0%) stopped anti-CGRP mAbs after 12.7±11.6months due to ineffectiveness (n=3) migraine sustained improvement (n=2) and AEs (n=1). MHDs significantly decreased from baseline (22.0±8.2) to the last follow-up (11.5±13.7) (p=0.002). EDSS score did not significantly change from the year before initiating anti-CGRP mAb (1.9±1.4) to baseline (1.9±1.4) and last follow-up (1.9±1.5)(p=0.497). Two patients (8.0%) had a clinical relapse, and one (4.0%) had MRI activity during treatment with anti-CGRP mAbs. Overall, DMTs were discontinued in two patients (8%). Mild AEs were reported in 2 PwMS (8.0%), none leading to discontinuation. Long-term treatment with anti-CGRP mAbs and DMTs for MS showed safety and effectiveness with no significant effect on MS disease course.

P-1960. Safety and Pharmacokinetics of Long-acting SARS-CoV-2 Antibodies Tixagevimab/Cilgavimab (AZD7442) are Consistent after Repeat Dosing: Results from the PROVENT Substudy

Abstract Background The SARS-CoV-2 antibody combination tixagevimab/cilgavimab (AZD7442) was efficacious in preventing COVID-19 over 6 months following a single 300 mg intramuscular (IM) dose in the PROVENT study. Participants included those that: (a) were immunocompromised and/or at increased risk for inadequate response to COVID-19 vaccination, or (b) were at increased severe COVID-19 risk. Following PROVENT, emergence of Omicron variants with reduced AZD7442 susceptibility prompted increase in the authorized dose and dosing frequency. Here, we report safety and pharmacokinetics (PK) of repeated doses of AZD7442 300–600 mg in participants who opted to continue in the PROVENT substudy. Methods Participants who entered the PROVENT open-label sub-study (NCT04625725) were assigned initially to 2 groups: Group 1 (n=234) received 1x AZD7442 300 mg in the parent study, then 1x 300 mg ∼10–14 months later (substudy Day 1). Group 2 (n=119) received placebo in the parent study, then 2x AZD7442 300 mg doses in the substudy. Group 3a (n=76) was a subset of Group 1 who received 2x 300 mg then 2x 600 mg doses. Group 3b (n=74) was a subset of Group 2 who received 1x 300 mg then 2x 600 mg doses (Table 1). The primary endpoint was safety; PK and antibodies to AZD7442 were also assessed. Results Baseline characteristics were overall similar across the groups. Adverse events (AEs) were reported in 75.7–81.5% and serious AEs in 13.2–16.8% of participants across the groups (Table 2). There were 14 deaths: 8 (3.4%) in Group 1, 5 (4.2%) in Group 2, and 1 (1.4%) in Group 3b. There was no clinically meaningful increase of AEs due to repeat doses of AZD7442 and no deaths were considered related to AZD7442. AZD7442 PK was consistent following redosing and between groups (Figure 1). The percentage of participants positive for treatment-emergent antibodies to AZD7442 was 10.5% (Group 1), 5.2% (Group 2), 10.7% (Group 3a), and 4.1% (Group 3b). Conclusion Safety and PK of AZD7442 were consistent after repeat dosing, regardless of whether participants initially received AZD7442 or placebo. These results will support future development of long-acting antibodies for pre-exposure prophylaxis against COVID-19. Disclosures Andrew Ustianowski, MD, PhD, AstraZeneca: Honoraria|Gilead: Honoraria|GSK: Honoraria|GSK: Speaker fees|Janssen: Honoraria|Janssen: Speaker fees|Merck: Honoraria|Merck: Speaker fees, Advisory Board|Pfiizer: Advisory Board|Sanofi: Honoraria|Sanofi: Speaker fees|ViiV Healthcare/GSK: Advisory Board Myron J. Levin, MD, CSL Seqirus USA: Advisor/Consultant|Curevo: Advisory Board|GSK: Grant/Research Support|GSK: Advisory Board|Moderna: Advisory Board|Pfizer: Advisory Board Stéphane De Wit, MD, AstraZeneca: Honoraria|AstraZeneca: Speaker fees|Gilead: Honoraria|Gilead: Speaker fees, Advisory Board|GSK: Honoraria|GSK: Speaker fees|Janssen: Honoraria|Janssen: Speaker fees|Merck: Honoraria|Merck: Speaker fees, Advisory Board|Pfizer: Advisory Board|Sanofi: Honoraria|Sanofi: Speaker fees|ViiV Healthcare/GSK: Advisory Board Odile Launay, MD, PhD, AstraZeneca: Principal investigator for the AstraZeneca-sponsored PROVENT study in France|AstraZeneca and other pharmaceutical companies: Honoraria|AstraZeneca and other pharmaceutical companies: Speaker fees Audrey Sharbaugh, PhD, AstraZeneca: Employee, holds or may hold stock Rohini Beavon, PhD, AstraZeneca: Employee, holds or may hold stock Jesse Thissen, MSc, AstraZeneca: Employee, holds or may hold stock Lauren Hirao, PhD, AstraZeneca: Employee, holds or may hold stock Vitalina Dzutseva, MD, PhD, AstraZeneca: Employee, holds or may hold stock Seth Seegobin, PhD, AstraZeneca: Employee, holds or may hold stock Katie Streicher, PhD, AstraZeneca: Employee of AstraZeneca and may own AstraZeneca stock or stock options. Alexandre Kiazand, MD, AstraZeneca: Employee, holds or may hold stock Mark T. Esser, PhD, AstraZeneca: Employee, holds or may hold stock Taylor Cohen, PhD, AstraZeneca: Employee, holds or may hold stock Lee-Jah Chang, MD, AstraZeneca: Employee of AstraZeneca John L. Perez, MD, AstraZeneca: Employee, holds or may hold stock

P-1969. Safety, Immunogenicity, and Pharmacokinetics of Repeat Dosing with AZD7442 (Tixagevimab/Cilgavimab): Final Analysis of the ENDURE Phase 2, Dose-Ranging Study in Immunocompromised Participants

Abstract Background Prior studies of the SARS-CoV-2 monoclonal antibody (mAb) combination AZD7442 (tixagevimab/cilgavimab) included limited numbers of immunocompromised (IC) participants, the target population for COVID-19 pre-exposure prophylaxis. We report repeat dosing data of AZD7442 in an IC population. Methods The randomized, open-label, ENDURE study (NCT05375760) enrolled individuals aged ≥ 18 yrs, weighing ≥ 40 kg, moderately to severely IC or at risk of inadequate vaccine response, and SARS-CoV-2–negative at baseline. Participants were randomized 1:1 to AZD7442 600 mg intramuscularly (IM) on Day 1 + 300 mg IM every 3 months (Arm A) or AZD7442 1200 mg intravenously on Day 1 + 600 mg IM every 6 months (Arm B). Month-12 dose was not administered due to non-safety related trial termination. Primary objectives were safety and immunogenicity (anti-drug antibodies; ADAs); secondary objectives were pharmacokinetics (PK) and SARS-CoV-2–neutralizing antibody (nAb) titers. Results Of 251 randomized participants, 124 were dosed in Arms A and B. Median exposure duration was 373.5 days in both arms. Participants’ mean age was 55.7 yrs, 53.2% were female, and 81.9% had not received a COVID-19 vaccine prior to study start. Adverse events (AEs) occurred in 84 (67.7%) participants in Arm A and 66 (53.2%) in Arm B. The proportion of participants with serious AEs (overall 9.3%) and AEs of special interest (3.1%) was similar across doses and following repeated dosing (Table 1). ADA incidence (% treatment-emergent ADA+) was similar in both arms (Arm A, 0.9%; Arm B, 2.7%) with no apparent impact of ADAs on safety, PK, or SARS-Cov-2 nAb titers (Table 2). Following dosing, mAb serum concentrations were stable in Arms A and B, with no accumulation observed (Figure 1). A strong correlation (R > 0.78) was observed between pseudovirus nAb titers and AZD7442 serum concentrations for both arms (Figure 2). Conclusion AZD7442 safety and ADA profiles were consistent across doses and dosing regimens. No accumulation in serum AZD7442 concentrations was observed with repeat dosing compared with the initial dose for each arm. These data may help inform development of future long-acting SARS-CoV-2 mAbs. Disclosures Taylor Cohen, PhD, AstraZeneca: Employee, holds or may hold stock Chigo Munthali, MBBS, MSc, DPM, MFPM, CCT(Pharma Med.), AstraZeneca: Employee, holds or may hold stock Herve Tchouakam Kouekam, MSc, Cytel Inc. (contracted to AstraZeneca): Employee of Cytel Inc. Sam Matthews, MSc, Exploristics Ltd. (contracted to AstraZeneca): Employee of Exploristics Ltd. Audrey Sharbaugh, PhD, AstraZeneca: Employee, holds or may hold stock Rohini Beavon, PhD, AstraZeneca: Employee, holds or may hold stock Dilki Wickramarachchi, PhD, AstraZeneca: Employee, holds or may hold stock Sharon Otal, HBSc, MBA, AstraZeneca: Employee, holds or may hold stock Haitao Yang, PhD, AstraZeneca: Employee, holds or may hold stock Anastasia A. Aksyuk, PhD, AstraZeneca: Employee, holds or may hold stock Lindsay E. Clegg, PhD, AstraZeneca: Employee, holds or may hold stock Huixia Zhang, PhD, AstraZeneca: Employee, holds or may hold stock Antonella Nadia Tuillio, MD, AstraZeneca: Employee, holds or may hold stock Seth Seegobin, PhD, AstraZeneca: Employee, holds or may hold stock Katie Streicher, PhD, AstraZeneca: Employee of AstraZeneca and may own AstraZeneca stock or stock options. David Wheeler, MD, AstraZeneca: Funding for clinical research|Gilead: Funding for clinical research|Janssen: Funding for clinical research Lee-Jah Chang, MD, AstraZeneca: Employee of AstraZeneca Hugh Montgomery, MD, AstraZeneca: Advisor/Consultant|Millfield Medical Ltd.: Advisor/Consultant|Millfield Medical Ltd.: Consulted for Millfield Medical Ltd during the development of a new Closed Circuit Continuous Positive Airway Pressure machine.|UK NIHR BRC at University College London Hospitals: Funding

P-1997. Real-world Effectiveness of Tixagevimab/cilgavimab for COVID-19 Pre-exposure Prophylaxis in Solid Organ Transplant Recipients during the BA.2.75 and BQ.1 Omicron Variant Period: A matched Case-control Dtudy

Abstract Background Solid organ transplant recipients (SOTRs) develop poor immunogenicity after SARS-CoV-2 immunization. The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab (T/C) has been shown to reduce the risk of COVID-19 among this vulnerable population. We assessed the effectiveness and safety of T/C pre-exposure prophylaxis (PrEP) for COVID-19 protection after transplantation. Methods We conducted a matched case-control study at a single transplant center during the Omicron lineages BA.2.75 and BQ.1 period (August 2022 to February 2023). T/C doses of 150/150 mg were provided from August 2022 until February 2023, and doses of 300/300 mg were administered thereafter (December 2022 to February 2023). All patients were followed for up to 6 months, and adverse events (AEs) from T/C were assessed. Results A total of 143 SOTRs were included, with 115 and 28 SOTRs in the T/C and control groups, respectively. Transplants included kidney (n=108), liver (n=28), and heart (n=9). Over 6 months, 18 (15.7%) in T/C developed COVID-19, with onset at median 3 months. All had mild infections without respiratory failure. Mild and reversible adverse events (AEs) were reported in 25.2% of cases. No rejection occurred. Non-significantly lower COVID-19 within 3 months during BA.2.75 Omicron (8.7% vs. 17.9% in control; p=0.128; effectiveness: 51.4%). At 6 months (BQ.1 Omicron), COVID-19 incidence was 15.7% in T/C vs. 17.9% in control (p=0.667; effectiveness: 12.3%). The occurrence of COVID-19 was not significantly different after adjustment for the number of vaccine doses, history of prior COVID-19, or the dose of T/C. Conclusion The effectiveness of T/C tends to be protective against susceptible strains, although the severity of breakthrough infections tends to be mild. Short-term safety as PrEP appears tolerable. TCTR20220801004. Disclosures All Authors: No reported disclosures

Synergistic Cancer Photoimmunotherapy by Harnessing Near‐Infrared‐Activated Nanoparticles Containing Charge Transfer Complexes

Phototherapy — which includes photothermal therapy (PTT) and photodynamic therapy (PDT) — has evoked interest as a promising cancer treatment modality on account of its noninvasiveness, spatiotemporal precision, and minimal side effects. C. Wang et al. recently reported a near‐infrared‐activated charge transfer complex‐based nanoparticle which consists of a donor (D) and an acceptor (A). Experimental results have demonstrated a potent immunotherapeutic effect of integrating programmed cell death protein 1 antibody combination therapy in preclinical models. Incorporating D–A interactions into nanosystems for photoimmunotherapy (PIT) is still a novel approach. This approach offers a multifaceted strategy for synergistic cancer PIT which holds promising potential to transform cancer treatment paradigms.

Synergistic Cancer Photoimmunotherapy by Harnessing Near-Infrared-Activated Nanoparticles Containing Charge Transfer Complexes.

Phototherapy - which includes photothermal therapy (PTT) and photodynamic therapy (PDT) - has evoked interest as a promising cancer treatment modality on account of its noninvasiveness, spatiotemporal precision, and minimal side effects. C. Wang et al. recently reported a near-infrared-activated charge transfer complex-based nanoparticle which consists of a donor (D) and an acceptor (A). Experimental results have demonstrated a potent immunotherapeutic effect of integrating programmed cell death protein 1 antibody combination therapy in preclinical models. Incorporating D-A interactions into nanosystems for photoimmunotherapy (PIT) is still a novel approach. This approach offers a multifaceted strategy for synergistic cancer PIT which holds promising potential to transform cancer treatment paradigms.

Fluorouracil enhances the anti-pancreatic cancer effect of anti-PD-L1 antibodies via up-regulating the expression of PD-L1 in cancer cells.

Pancreatic cancer is characterized by occult onset, low early diagnosis rate, rapid progress, and poor prognosis. Due to the low response rate and low programmed cell death ligand 1 (PD-L1) expression in pancreatic cancer, the therapeutic application of PL-L1 inhibitors in pancreatic cancer is greatly limited. In vitro studies showed that the expression of PD-L1 increased in pancreatic cancer cells stimulated by fluorouracil (5-FU). We aim to explore the combined effect of 5-FU and anti-PD-L1 antibodies and to provide a reference for the clinical application of PD-L1 antibodies in pancreatic cancer. In the current study, male BALB/c mice were adopted to construct a tumor-bearing model of pancreatic cancer cells. 5-FU and anti-mouse PD-L1 antibodies were combined and administered to evaluate their synergistic effects. The enhancing immune cytotoxicity effect of 5-FU sensitizing the anti-PD-L1 antibody in vivo and in vitro was analyzed by immunohistochemistry and western blot assays. Results showed that 5-FU and anti-PD-L1 antibody combination increased the expression of PD-L1 and IFN-γ, and infiltration of CD8+ T lymphocytes in pancreatic xenograft tumor tissues, which was proven by immunohistochemistry and western analysis. Moreover, the combination with the 5-FU remarkably enhanced the immune cytotoxicity of anti-PD-L1 antibodies in mice. In vitro analysis demonstrates that 5-FU increases the expression of PD-L1 on the surface of pancreatic cancer cell lines via up-regulating nuclear factor kappa B (NF-κB) and Protein kinase B (AKT) pathways. This synergistic effect could be abolished by NF-κB and AKT inhibitors.

Broad-spectrum efficacy of CEACAM6-targeted antibody-drug conjugate with BET protein degrader in colorectal, lung, and breast cancer mouse models.

Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC, 84-EBET) for pancreatic cancer by using the carcinoembryonic-antigen-related cell-adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. Here, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers (CRC, LC, BC) and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of CRC, LC, and BC revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E (MMAE)-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of CRC-, LC-, and BC-patient-derived xenograft tumors and cell-line-derived xenograft tumors. Moreover, in mouse syngeneic CRC, LC, and BC models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded BRD4 protein in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.

Mechanisms and optimization strategies for the occurrence of antibody-drug conjugate toxicity

Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted cancer therapies, with 13 ADCs approved by the FDA and over 140 undergoing clinical research. ADCs are designed to enhance the selective delivery of cytotoxic drugs to tumor cells through high-affinity monoclonal antibodies (mAbs), improving the therapeutic index of the drug. Despite their potential, ADCs face significant challenges related to toxicity, including hematologic, ocular, skin, and neurological side effects, which limit their clinical application. This review provides an in-depth analysis of the mechanisms underlying ADC toxicity, which includes both targeted and off-target effects that can damage normal cells and tissues. Strategies for optimizing ADC safety, such as improving antibody structure, effector molecules, linkers, and combination therapies, are discussed. The review emphasizes the need for continued research to address these challenges and reduce off-target toxicity while enhancing the efficacy of ADCs, paving the way for the development of safer and more effective next-generation ADC drugs.

Pair combinations of human monoclonal antibodies fully protected mice against bunyavirus SFTSV lethal challenge.

Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever caused by a tick-borne virus SFTSV with a mortality rate of up to 30%. Currently, there is no vaccine or effective therapy for SFTS. Neutralizing monoclonal antibody therapy, which provides immediate passive immunity and may limit disease progression, has emerged as a reliable approach for developing therapeutic drugs for SFTS. In this study, 4 human monoclonal antibodies (hmAbs) derived from convalescent SFTS patients' lymphocytes based on human single-chain variable fragment antibody libraries were tested for their neutralizing activities in cells and their treatment effect in animals individually and in pair combinations. The neutralization test showed that all 4 hmAbs exhibited strong neutralizing activity against SFTSV infection in vitro. The protection rate of hmAbs 4-6, 1F6, 1B2, and 4-5 against SFTSV lethal challenge in IFNAR1-/- A129 mice are 50%, 16.7%, 83.3%, and 66.7%, respectively. Notably, the pair combination of antibodies (1B2 and 4-5, 1B2 and 1F6) that recognized distinct epitopes protected 100% of mice against SFTSV lethal challenge. In conclusion, our findings indicate that the pair combinations of hmAbs 1B2 and 4-5 or hmAbs 1B2 and 1F6 may serve as promising therapeutic drugs for treating SFTSV infection.

Regimen Selection for Chemoimmunotherapy in Nonsquamous Non-Small Cell Lung Cancer with Low PD-L1 Expression: A Multicenter Retrospective Cohort Study.

Although chemoimmunotherapy is recommended for advanced nonsquamous non-small cell lung cancer (NSCLC) with low programmed cell death ligand 1 (PD-L1) expression, no head-to-head comparisons of immune checkpoint inhibitors (ICIs) have been performed. Therefore, we compared the effect and safety of regimens in these patients to guide evidence-based treatment. This retrospective study included patients with advanced nonsquamous NSCLC with a PD-L1 tumor proportion score of 1% to 49% administered ICI combination platinum-based chemotherapy between May 2018 and May 2023 at 19 institutions in Japan. The main analysis compared survival outcomes and the incidence of grade ≥3 adverse events among regimens. Among 316 included patients (median [range] age, 69 [36-89] years; 242 males; 41 never smokers), 200 (63%), 68 (22%), and 48 (15%) received chemotherapy combined with anti-programmed cell death protein 1 (PD-1), anti-PD-L1, and anti-PD-1/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies, respectively. The median overall survival times were 28.6, 23.1, and 24.4 months (P = .41), and the median progression-free survival times were 9.4, 7.2, and 8.7 months (P = .28) in the anti-PD-1/Chemo, anti-PD-L1/Chemo and anti-PD-1/CTLA-4/Chemo groups, respectively. The anti-PD-1/CTLA-4/Chemo group had the lowest incidence of hematologic toxicity (P = .13) and the highest incidence of nonhematologic toxicity (P = .07). The incidence of grade ≥3 pneumonitis was significantly lower in the anti-PD-L1/Chemo group (P = .049). Despite comparable survival benefits, adverse events differed among three regimens in patients with low PD-L1 expression. Notably, anti-PD-L1 antibody combination chemotherapy may reduce the risk of severe pneumonitis.

Current transcriptome database and biomarker discovery for immunotherapy by immune checkpoint blockade.

Immune checkpoint blockade (ICB) has revolutionized the current immuno-oncology and significantly improved clinical outcome for cancer treatment. Despite the advancement in clinics, only a small subset of patients derives immune response to the ICB therapy. Therefore, a robust predictive biomarker that identifies potential candidate becomes increasingly crucial in delivering this technology to the public. In this review, we first discuss the biomarkers that focus on tumor genome, tumor microenvironment and tumor-host interaction. Then, we compare existing databases for biomarker discovery for ICB response. We also present IOhub - an interactive web portal that incorporates 36 bulk and 10 single-cell transcriptome datasets for benchmark analysis of the current biomarkers. Finally, we highlight the trending interest in antibody drug conjugate and combination treatment and their use in precision immuno-oncology.

Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

An Improved Theileria parva Sporozoite Seroneutralization Assay for the Identification of East Coast Fever Immune Correlates.

Immune correlates of protection are ideal tools to predict treatment or vaccine efficacy. However, the accuracy of the immune correlate and the capability to robustly predict the outcome of a vaccine candidate are determined by the performance of the in vitro immunoassay used. Several Theileria parva sporozoite seroneutralization assays have previously been used to assess antibody functional activities; however, a common limitation has been the need for fresh material, target cells and sporozoites, and operator-to-operator bias. An improved assay represents a positive step toward overcoming challenges associated with variability and it might provide a more reliable means of establishing an immune correlate with protection after sub-unit vaccine administration. Herein, we describe key improvements, among them, (1) the use of frozen parasites and target cells to avoid batch-to-batch variations and (2) the development of a new assay read-out based on the detection of infected cells through flow cytometry, instead of the use of Giemsa staining and microscopic evaluation, in order to improve the reproducibility of the results. The improved seroneutralization assay is not only able to detect the individual neutralizing capacity of antibodies; it also detects the additive effect of antibody combinations. This effect is described for the first time in Theileria parva and is of great interest for new antigen discovery and/or the epitope discovery of already known antigens like p67, opening a new avenue for the identification of ECF immune correlates of protection and the in vitro down-selection of new Theileria parva vaccine candidates, thereby contributing to reducing the use of animals in challenge experiments.

PPARδ Antagonist Inhibited CD47 Expression and Phagocytosis.

Increasing evidence suggests that CD47 is highly expressed in multiple types of cancer, which could bind to SIRPα on macrophage, leading to inhibition of macrophage phagocytosis and promotion of tumor growth. However, the regulatory mechanism of CD47 gene expression is not completely clear. Our results indicated that colon cancer cells treated with GSK0660 drug, which is one of the PPARδ antagonists, significantly reduced CD47 gene and protein expression levels in a time and dose-dependent manner. CD47 reporter plasmid was constructed and dual-luciferase analysis was performed. The results suggest that GSK0660 treatment markedly reduced CD47 gene transcriptional activity. Moreover, co-cultured analysis showed that GSK0660 treatment increased phagocytosis. BALB/C mice implanted with CT-26 colon cancer cells were treated with GSK0660, and the results showed that GSK0660 significantly inhibited tumor growth. Moreover, the combination of CD47 monoclonal antibody with GSK0660 drug significantly inhibited tumor growth compared to GSK0660 or CD47 antibody treatment alone. These findings suggest that GSK0660 synergized with CD47 antibody to enhance antitumor immunotherapy.

Deficiencies of Inducible Costimulator (ICOS) During Chronic Infection with Toxoplasma gondii Upregulate the CD28-Dependent Cytotoxicity of CD8+ T Cells and Their Effector Function Against Tissue Cysts of the Parasite.

We recently identified that the cerebral mRNA expression of inducible costimulator (ICOS) and its ligand, ICOSL, both significantly increase during the elimination of Toxoplasma gondii cysts from the brains of infected mice by the perforin-mediated cytotoxic activity of CD8+ T cells. In the present study, we examined the role of ICOS in activating the effector activity of CD8+ T cells in response to the presence of cysts in infected mice. Following the adoptive transfer of splenic CD8+ T cells from chronically infected ICOS-deficient (ICOS-/-) and wild-type (WT) mice to infected SCID mice, fewer CD8+ T cells were detected in the brains of the recipients of ICOS-/- CD8+ T cells than the recipients of WT CD8+ T cells. Interestingly, even with the lower migration rate of the ICOS-/- CD8+ T cells, those T cells eliminated T. gondii cysts more efficiently than WT CD8+ T cells did in the brains of the recipient mice. Consistently, the ICOS-/- CD8+ T cells secreted greater amounts of granzyme B in response to T. gondii antigens in vitro than WT CD8+ T cells did. We identified that CD8+ T cells of infected ICOS-/- mice express significantly greater levels of CD28 on their surface than CD8+ T cells of infected WT mice, and the relative expression of CD28 mRNA to CD8β mRNA levels in the brains of the recipients of those CD8+ T cells were strongly correlated with their relative expression levels of mRNA for T-bet transcription factors and perforin. Furthermore, blocking CD28 signaling using a combination of anti-CD80 and anti-CD86 antibodies eliminated the increased cytotoxic activity of the ICOS-/- CD8+ T cells in vitro. The present study uncovered notable compensatory interactions between ICOS and CD28, which protected the cytotoxic effector activity of CD8+ T cells against microbial infection in a murine model of chronic infection with T. gondii.

Hormone therapy enhances anti-PD1 efficacy in premenopausal estrogen receptor-positive and HER2-negative advanced breast cancer.

The efficacy of immunotherapy for estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC) has not been proven. We conduct a phase 1b/2 trial to assess the efficacy of combining pembrolizumab (anti-PD1 antibody), exemestane (nonsteroidal aromatase inhibitor), and leuprolide (gonadotropin-releasing hormone agonist) for 15 patients with premenopausal ER+/HER2- MBC who had failed one to two lines of hormone therapy (HT) without chemotherapy. The primary endpoint of progression-free survival rate at 8months (i.e., 64.3%) is achieved. Moreover, 5 of the 14 evaluable subjects exhibited partial responses (overall response rate= 35.7%). The combination of anti-PD1 antibody and anti-hormone therapy is associated with an enhanced immunoreactive microenvironment influencing treatment efficacy, as observed in pre- and post-treatment tumor samples through NanoString analysis. Post-treatment tumors are associated with increased immune response and immune cells. The findings indicate that combining HT with anti-PD1 antibody is a promising treatment strategy for patients with premenopausal ER+/HER2- MBC. This study was registered at ClinicalTrials.gov (NCT02990845).

Developing a human monoclonal antibody combination CRM25 to prevent rabies after exposure

Immunization against rabies post-exposure prophylaxis (PEP) requires passive immunization with either monoclonal antibody (mAb) or blood-derived rabies immunoglobin (RIG). Currently, replacing traditional RIG with emerging mAb or mAb combinations is highly recommended due to the limited supply and potential safety risks of RIG. Here, we developed a mAb combination named CRM25 by combining two human mAbs, RM02 and RM05, at a 1:1 mass ratio. RM02 and RM05 were non-competing and non-overlapping mAbs targeting epitopes I and III, respectively. K226 and G229 were found to be the critical amino acid sites for RM02 neutralization, but the mutant I338T displayed decreased susceptibility to RM05 neutralization. Notably, CRM25 was capable of cross-neutralizing rabies virus (RABV) strains containing K226M or I338T mutations. CRM25 additionally showed an inhibitory effect on the infection of all tested common RABVs and non-RABV phylogroup I lyssaviruses. CRM25 not only exhibited neutralizing activity but also exhibited antiviral effects via Fc-mediated effector functions. Importantly, CRM25 was comparable to human RIG in terms of its capacity to protect Syrian golden hamsters from lethal RABV challenges. These findings promote more thorough research on CRM25′s antiviral properties in cells and in vivo to enhance its clinical applicability and suggest that it may be a viable candidate medication for rabies PEP.