High-affinity Human Monoclonal Antibody Research Articles

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Immunogenicity, Safety, and Tolerability After Subcutaneous Administration of Tozorakimab in Healthy Chinese Participants.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24kg/m2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300mg [2mL] or 600mg [4mL]) or matching placebo (2 or 4mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7μg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.

654 Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ > grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study > 90 days and > 180 days in > 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (> 90 days for > 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .

APG777, a High-Affinity Humanized IgG1 Monoclonal Antibody Targeting IL-13, Demonstrates Prolonged Half-Life in Non-Human Primates

APG777, a High-Affinity Humanized IgG1 Monoclonal Antibody Targeting IL-13, Demonstrates Prolonged Half-Life in Non-Human Primates

Effects of secukinumab combined with tretinoin on metabolism, liver enzymes, and inflammatory factors in patients with moderate to severe psoriasis vulgaris.

Psoriasis is a T cell-mediated polygenic chronic inflammatory disease. Interleukin (IL)-17A plays a major role in psoriasis pathogenesis. Secukinumab is a high-affinity human monoclonal antibody against IL-17A. This article explored efficacy and safety of secukinumab plus tretinoin in moderate to severe psoriasis (MSP) vulgaris, and assessed metabolism, liver function, and inflammation. A total of 135 patients diagnosed with moderate or severe psoriasis vulgaris were enrolled and randomized into three groups at a 1 : 1 : 1 ratio, receiving treatment with rretinoin, secukinumab, or combination therapy for a duration of 16 weeks. Psoriasis area and severity index (PASI) scores, serum T lymphocyte subsets, glucose, lipid, and uric acid (UA) metabolism, liver enzymes, and inflammatory factors (IFs) were measured. Following the therapy, subjects had decreased PASI scores, increased serum CD3+, CD4+, and CD4+/CD8+, decreased serum CD8+, and decreased serum UA and IL-2, IL-6, IL-23, interferon-γ (IFN-γ), and tumor necrosis factor (TNF)-α (p < 0.05). Total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, apolipoproteins A1, B, fasting blood glucose, alanine transaminase, aspartate transaminase, and alkaline phosphatase had no obvious differences among the subjects (p > 0.05). As against the Tretinoin and the Secukinumab groups, the PASI score was visiblysmaller, the changes in serum T lymphocyte subsets were more obvious, and serum UA and IFs were lower in the Combination group following the therapy (p < 0.05). Secukinumab combined with tretinoin is more effective in MSP vulgaris, which can visibly reduce inflammatory response without affecting glucose and lipid metabolism and liver function.

A Randomized Double-Blind Placebo-Controlled Phase II Multi-Center Study of Inflammation Modification of Canakinumab to Prevent Leukemic Progression of Clonal Cytopenias of Unknown Significance (CCUS): Impact Study

Background and Significance: High-risk Clonal Cytopenia of Undetermined Significance (HR-CCUS) is defined by prolonged cytopenias (&amp;gt; 4 months) in 1 or more cell lineages plus myeloid-disorder-associated mutations. CCUS patients with spliceosome mutations, DNMT3A, TET2, or ASXL1 mutations in combination with at least 2 other somatic mutations appear to have an extremely high rate of progression to myeloid neoplasms (MN) with a 95% 5-year cumulative probability of developing a MNsuch asMDS, MPN, or AML (13-fold increased risk compared to patients with cytopenia classified). Several studies implicate the inflammasome in CH progression to MDS/AML. Interleukin (IL)-1β is a key upstream cytokine in the inflammasome that strongly induces IL-6. Mutations in another key protein in the inflammasome, cryopyrin, result in high systemic levels of IL-1β and are associated with auto-inflammatory diseases. We hypothesize that the preclinical and clinical data showing a benefit of IL-1β inhibition in patients with CH, is due to reduced downstream activations of inflammasome proteins. Canakinumab is a high-affinity human monoclonal anti-human IL-1β antibody- FDA approved for the treatment of IL-1β driven inflammatory and oncologic diseases. By binding specifically to human IL-1β, canakinumab blocks the interaction of IL-1β with the IL-1 receptor, leading to inhibition of its downstream targets, thereby preventing IL-1β-induced gene activation and the production of inflammatory mediators. A phase II clinical trial investigating the use of canakinumab in combination with azacitidine is currently studying the impact canakinumab may have on disease progression in relapsed/refractory low or intermediate risk MDS patients (NCT04239157). This has now been extended to newly diagnosed MDS as new emerging data looks promising [unpublished data]. No significant toxicities have been reported. Thus, we hypothesize that the treatment of HR-CCUS patients, for whom there is no current disease modifying therapy, with an inflammasome targeting antibody, would prevent or significantly delay development of a MN, improve cytopenias and decrease the clone size as well as prevent further clonal evolution. Study Design and Methods: This study (NCT05641831) is a Phase II multicenter, randomized, two-arm, double-blind placebo-controlled study in patients with HR-CCUS (Figure 1). Patients with HR-CCUS, no known hematological malignancy, and any mutational combination as deemed appropriate by the inclusion criteria - are randomized to the study Arm or control Arm. Patients assigned to the study arm will be eligible to receive canakinumab, 300 mg subcutaneously every 3 months for 2 years. Patients assigned to the control arm will receive placebo every 3 months for 2 years. Bone marrow biopsies will be done for both arms every 6 months to monitor for disease progression (WHO 2016). PB samples will be collected every 3 months to monitor for disease progression. Patient-reported outcomes will be collected at the time of disease assessment. Statistical plan: The null hypothesis assumes the time to overt MN (MDS/MPN/CMML/AML) is equal in the control and study arms (H 0: HR=1) versus the alternative hypothesis that the risk of an event is lower in the study arm (H 1: HR&amp;lt;1). Assuming exponential survival, 71 events (overt MN) are required for the final analysis to detect a hazard ratio of 0.55 (median 2 years for the control arm versus 3.636 years for the study arm) using a log-rank test with 80% power and one-sided significance level of 5%. This includes one interim futility analysis when 50% of the targeted number of events (36) have been observed. At the time of the interim analysis, futility will be declared if the hazard ratio is greater than 1 and in favor of the control arm. The futility boundary is statistically non-binding in that there is not a final significance level adjustment. If the futility boundary is crossed, then the study will terminate early; patients randomized to the control arm will continue standard of care off study and patients randomized to the study arm will discontinue treatment with Canakinumab. Accounting for 5% drop-out, this calculation assumes accrual of 89 patients over 3 years and a minimum follow-up of 5 years (or until withdrawal, death, or study closure; earliest event). To date, 5 patients have been randomized and enrolled on study (Table 1).

Features and protective efficacy of human monoclonal antibodies targeting Mycobacterium tuberculosis arabinomannan.

A better understanding of the epitopes most relevant for antibody-mediated protection against tuberculosis (TB) remains a major knowledge gap. We have shown that human polyclonal IgG to the Mycobacterium tuberculosis (Mtb) surface glycan arabinomannan (AM) and related lipoarabinomannan (LAM) is protective against TB. To investigate the impact of AM epitope recognition and Fc-gamma receptor (FcgR)-binding on antibody functions against Mtb, we isolated a high-affinity human monoclonal antibody (mAb; P1AM25) to AM and show its binding to oligosaccharide (OS) motifs we previously found to be associated with in vitro functions of human polyclonal anti-AM IgG. Human IgG1 P1AM25, but not two other high-affinity human IgG1 anti-AM mAbs reactive with different AM OS motifs, enhanced Mtb phagocytosis by macrophages and reduced intracellular growth in an FcgR-dependent manner. P1AM25 in murine IgG2a, but neither murine IgG1 nor a non-FcgR-binding IgG, given intraperitoneally prior to and after aerosolized Mtb infection was protective in C57BL/6 mice. Moreover, we demonstrate the protective efficacy of human IgG1 P1AM25 in passive transfer with Mtb-infected FcgR-humanized mice. These data enhance our knowledge of the important interplay between both antibody epitope specificity and Fc effector functions in the defense against Mtb and could inform development strategies of vaccines against TB.

LATIFY: Phase 3 study of ceralasertib + durvalumab vs docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer that progressed on or after anti-PD-(L)1 and platinum-based therapy.

TPS9161 Background: Following progression on first- or second-line immunotherapy ± platinum-based chemotherapy (CT), the prognosis for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) is poor with limited alternative options to docetaxel. Ceralasertib is a selective inhibitor of Ataxia Telangiectasia and Rad3-related (ATR) protein kinase, which is activated in response to DNA damage. Clinical data suggest that ceralasertib may sensitize tumors to immunotherapy by biasing T cells to an immune-effective phenotype. Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that binds programmed cell death ligand-1 (PD-L1) and inhibits PD-L1-mediated suppression of T-cell activation. Combining ceralasertib with durvalumab may amplify the antitumor immune response, and potentially lead to durable tumor control. In the ongoing phase 2 HUDSON study in pts with locally advanced or metastatic NSCLC who progressed on anti-PD-(L)1 therapy and platinum-doublet regimen, ceralasertib + durvalumab showed promising efficacy with median progression-free survival (PFS) of 6.0 mos (80% CI, 4.6–7.5) and median overall survival (OS) of 15.9 mos (80% CI, 14.1–20.3). Methods: LATIFY is a phase 3, open-label, randomized, multicenter study in pts with NSCLC (NCT05450692). Key inclusion criteria are age ≥18 years; ECOG performance status 0–1; documented EGFR and ALK wild-type, and tumor cell PD-L1 status; and adequate organ and bone marrow function. Stable brain metastases are allowed. Pts should be eligible for second- or third-line therapy, and must have received an anti-PD-(L)1 therapy and a platinum-containing doublet regimen for locally advanced or metastatic NSCLC either separately or in combination, but no other prior therapies. Key exclusion criteria include mixed small-cell lung and NSCLC histology, unresolved toxicities of Grade ≥2 (NCI CTCAE v5.0) from prior therapy, active or prior autoimmune or inflammatory disorders, &gt; 1 line of prior anti-PD-(L)1 therapy (alone or in combination), and &gt; 1 line of platinum-based CT in a metastatic setting. Pts are randomized 1:1 to receive either oral ceralasertib 240 mg twice daily on Days (D) 1–7 with IV durvalumab 1500 mg on D8 (28-day cycle) or IV docetaxel 75 mg/m2 (D1, 21-day cycle). The primary objective is to assess efficacy by OS. Secondary objectives include evaluating efficacy by PFS, objective response rate and disease control rate by RECIST v1.1; duration of, and time to, response; time to second progression or death; OS at 12 mos; time to deterioration of health-related quality of life and physical function; determining the pharmacokinetics of ceralasertib; and assessing safety. Approximately 580 pts will be recruited from around 21 countries in the Americas, Europe, and Asia Pacific. Clinical trial information: NCT05450692 .

A phase II trial with safety lead-in to evaluate the addition of sotigalimab, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin for the treatment of advanced sarcoma.

11565 Background: Immune checkpoint inhibitors have limited efficacy in soft tissue sarcoma (STS) due to insufficient T-cell activation and infiltration by immunosuppressive macrophages. Sotigalimab (S), a high-affinity humanized monoclonal antibody for CD40, promotes antigen presentation, stimulates T-cell responses, and reprograms immunosuppressive macrophages. Preclinical studies with CD40 agonists revealed efficacy in immune “cold” tumor types and synergy with chemotherapy. Standard first-line doxorubicin (D) provides objective response rate (ORR) &lt; 15% and median progression free survival (mPFS) of 4-6 mos in advanced STS. We therefore conducted this first-in-human study of D+S in STS. Methods: An open-label, single-arm, multi-center, phase 2 study evaluated D+S in advanced STS. Pts had ECOG PS ≤ 1 and any number of prior lines (but were anthracycline-naïve). The study initially enrolled all STS subtypes (except KS and GIST) but was amended in 12/2020 to limit enrollment to dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), and undifferentiated pleomorphic sarcoma (UPS). Pts received D 75 mg/m2 IV D1 + S 0.3 mg/kg IV D1 for eight 21-day cycles, followed by S monotherapy. A safety lead-in was performed (first 6 patients). Primary endpoint was ORR. Secondary endpoints included PFS and safety. A Simon two-stage design was used. If ≥ 7/32 responded overall, the treatment would be considered promising (85% power, α = 0.05). A subset of patients underwent paired tumor biopsies. Results: 32 pts have enrolled (median age 62; 10 LMS, 10 UPS, 9 DDLPS, 3 other). 4 pts remain on treatment with median follow-up of 2.8 mos (1 UPS pt has not reached first imaging). D (75 mg/m2) + S (0.3 mg/kg) was safe and tolerable without dose limiting toxicity. Overall ORR was 16% (5/31). Objective responses occurred in UPS (2), LMS (1), other LPS (1), and epithelioid hemangioendothelioma (1). Overall mPFS was 7.5 mos (95% CI 5.6-14.9 mos) and PFS rate at 6 and 12-mos was 55% and 31%, respectively. mPFS by STS subtype was 11.9 mos (95% CI: 10.3 – NE) for DDLPS, 7.5 mos (95% CI: 1.4—NE) for UPS and 5.6 mos (95% CI: 1.3 – NE) for LMS. Overall, 17/31 (55%) pts experienced grade 3 or 4 adverse events (AEs): most commonly, neutropenia (32%), febrile neutropenia (19%), and anemia (16%). 16% of pts experienced cytokine release (all low-grade). Correlative analysis of biopsies with high-definition spatial proteomics is ongoing. Conclusions: D (75 mg/m2) + S (0.3 mg/kg) every 21 days is safe and tolerable in STS. Final analysis of the primary endpoint awaits further follow-up on recently enrolled patients. Subtype-specific analysis suggests improvement in median PFS for DDLPS over historical controls: 11.9 mos vs 4 mos (Stacchiotti S. Ann Oncol 2020; Livingston M. Sci Rep 2017). An expansion of the DDLPS cohort is planned. Clinical trial information: NCT03719430 .

Characterization of the C6D7-RBD Human Monoclonal Antibody Specific to the SARS-CoV-2 S Protein Receptor-Binding Domain.

The new coronavirus infection COVID-19 is an acute viral disease that affects primarily the upper respiratory tract. The etiological agent of COVID-19 is the SARS-CoV-2 RNA virus (Coronaviridae family, Betacoronavirus genus, Sarbecovirus subgenus). We have developed a high-affinity human monoclonal antibody, called C6D7-RBD, which is specific to the S protein receptor-binding domain (RBD) from the SARS-CoV-2 Wuhan-Hu-1 strain and exhibits virus-neutralizing activity in a test with recombinant antigens: angiotensin-converting enzyme 2 (ACE2) and RBD.

Delayed administration of elezanumab, a human anti-RGMa neutralizing monoclonal antibody, promotes recovery following cervical spinal cord injury

Spinal cord injury (SCI) elicits a cascade of degenerative events including cell death, axonal degeneration, and the upregulation of inhibitory molecules which limit repair. Repulsive guidance molecule A (RGMa) is an axon growth inhibitor which is also involved in neuronal cell death and differentiation. SCI causes upregulation of RGMa in the injured rodent, non-human primate, and human spinal cord. Recently, we showed that delayed administration of elezanumab, a high affinity human RGMa-specific monoclonal antibody, promoted neuroprotective and regenerative effects following thoracic SCI. Since most human traumatic SCI is at the cervical level, and level-dependent anatomical and molecular differences may influence pathophysiological responses to injury and treatment, we examined the efficacy of elezanumab and its therapeutic time window of administration in a clinically relevant rat model of cervical impact-compression SCI. Pharmacokinetic analysis of plasma and spinal cord tissue lysate showed comparable levels of RGMa antibodies with delayed administration following cervical SCI. At 12w after SCI, elezanumab promoted long term benefits including perilesional sparing of motoneurons and increased neuroplasticity of key descending pathways involved in locomotion and fine motor function. Elezanumab also promoted growth of corticospinal axons into spinal cord gray matter and enhanced serotonergic innervation of the ventral horn to form synaptic connections caudal to the cervical lesion. Significant recovery in grip and trunk/core strength, locomotion and gait, and spontaneous voiding ability was found in rats treated with elezanumab either immediately post-injury or at 3 h post-SCI, and improvements in specific gait parameters were found when elezanumab was delayed to 24 h post-injury. We also developed a new locomotor score, the Cervical Locomotor Score, a simple and sensitive measure of trunk/core and limb strength and stability during dynamic locomotion.

Monoclonal antibody Daratumumab promotes macrophage-mediated anti-myeloma phagocytic activity via engaging FC gamma receptor and activation of macrophages.

Daratumumab (DAR) is novel human anti-CD38 IgG1, high-affinity human monoclonal antibody having broad-spectrum killing activity. The antibody is recommended to treat multiple myeloma. Recently Antibody-dependent cellular phagocytosis (ADCP) have been identified as the potential mechanism of DAR in addition to complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). In the present study we evaluated the effect of Daratumumab on other effector cells of multiple myeloma. Luciferase+ MM.1R GFP cells were selected for the study. For immune-compromised multiple myeloma tumour xenograft mouse model we used severe combined immunodeficient beige (SCID-beige), NOD SCID gamma (NSG) and C57Bl/6j mice. Bioluminescence imaging was carried by injecting luciferin, and in vivo confocal microscopy was done for tracing bone marrow niches. Spleen and tumours were submitted to immunophenotypic analysis. MTT assay was done for cell proliferation studies. We established tumour xenograft mouse model. It was found that DAR showed significant anti-tumour effect in tumour xenograft multiple myeloma mice. We found that DAR showed anti-tumour activity via Fc-FcγR interaction with macrophages. DAR induced phenotypic activation of macrophages in mice and resulted in ADCP of cancerous cells via interacting Fc-FcγR in vitro. The study suggested that DAR exerted anti-tumour activity in multiple myeloma by interacting with Fc-FcγR.

Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity.

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.

Ligelizumab for adolescent patients with CSU: first results from a dedicated Phase 2b study

The first results of the dose-finding Phase-2b study of ligelizumab, a next-generation high-affinity humanized monoclonal anti-IgE antibody, in adolescent chronic spontaneous urticaria (CSU) are reported here.

High affinity human Fc specific monoclonal antibodies for capture kinetic analyses of antibody-antigen interactions

We recently demonstrated that capturing human monoclonal antibodies (hmAbs) using high affinity anti-human Fc (AHC) antibodies allows reliable characterization of antibody-antigen interactions. Here, we characterized six human Fc specific mouse monoclonal antibodies (mAbs) and compared their binding profiles with three previously characterized goat AHC polyclonal antibodies (pAbs), exhibiting properties of a good capture reagent. All six mouse AHC mAbs specifically bound with high affinity to the Fc region of hIgG1, hIgG2, hIgG4 and to 43 different hIgG variants, containing substitutions and/or mutations in the hinge and/or Fc region, that have been reported to exhibit modified antibody effector function and/or pharmacokinetics. Biacore sensor surfaces individually derivatized with mouse AHC mAbs exhibited >2.5-fold higher hIgG binding capacity compared to the three goat AHC pAb surfaces and reproducibly captured hIgG over 300 capture-regeneration cycles. The results of the capture kinetic analyses performed on 31 antibody-antigen interactions using surfaces derivatized with either of the two highest affinity AHC mAbs (REGN7942 or REGN7943) were in concordance with those performed using goat AHC pAb surfaces. Our data demonstrate that AHC mAbs such as REGN7942 and REGN7943 that have properties superior than the three goat AHC pAbs are highly valuable research reagents, especially to perform capture kinetic analyses of antibody-antigen interactions on optical biosensors.

Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy; An Open-Label, Multicenter, Phase 1b Study

Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy; An Open-Label, Multicenter, Phase 1b Study

Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.

Use of nicotine-specific monoclonal antibodies (mAbs) to sequester and reduce nicotine distribution to brain has been proposed as a therapeutic approach to treat nicotine addiction (the basis of tobacco use disorder). A series of monoclonal antibodies with high affinity for nicotine (nic•mAbs) was isolated from B-cells of vaccinated smokers. Genes encoding 32 unique nicotine binding antibodies were cloned, and the mAbs expressed and tested by surface plasmon resonance to determine their affinity for S-(–)-nicotine. The highest affinity nic•mAbs had binding affinity constants (KD) between 5 and 67 nM. The 4 highest affinity nic•mAbs were selected to undergo additional secondary screening for antigen-specificity, protein properties (including aggregation and stability), and functional in vivo studies to evaluate their capacity for reducing nicotine distribution to brain in rats. The 2 most potent nic•mAbs in single-dose nicotine pharmacokinetic experiments were further tested in a dose-response in vivo study. The most potent lead, ATI-1013, was selected as the lead candidate based on the results of these studies. Pretreatment with 40 and 80 mg/kg ATI-1013 reduced brain nicotine levels by 56 and 95%, respectively, in a repeated nicotine dosing experiment simulating very heavy smoking. Nicotine self-administration was also significantly reduced in rats treated with ATI-1013. A pilot rat 30-day repeat-dose toxicology study (4x200mg/kg ATI-1013) in the presence of nicotine indicated no drug-related safety concerns. These data provide evidence that ATI-1013 could be a potential therapy for the treatment of nicotine addiction.

Abstract 1841: IMGC936, an investigational ADAM9-targeting antibody drug conjugate, is active against patient-derived ADAM9-expressing xenograft models

Abstract Background: A disintegrin and metalloprotease (ADAM) 9 is a member of the ADAM family of transmembrane proteins. ADAM9 overexpression correlates with tumor progression, metastasis and poor prognosis in multiple cancers. IMGC936, an ADAM9-targeting antibody drug conjugate (ADC), is comprised of a high-affinity humanized monoclonal antibody site-specifically coupled to DM21 at a drug-antibody ratio of 2.0. DM21 is a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker. IMGC936 is in a phase 1 dose escalation study evaluating safety and pharmacokinetics in cancer patients. The goals of this study were: 1) to explore ADAM9 expression in various solid tumors, and 2) to evaluate the activity of IMGC936 in clinically relevant patient-derived xenograft (PDX) models with ADAM9 expression similar to that observed in human tumors. Methods: ADAM9 expression was evaluated on primary patient and PDX formalin-fixed, paraffin-embedded samples with the anti-ADAM9 antibody D64B5 (Cell Signaling Technology). Expression of ADAM9 was quantitated by H-score to capture the frequency and intensity of staining. Mice bearing PDX tumors were dosed once at 8.6 mg/kg of IMGC936, which delivered 100 µg/kg of DM payload. Anti-tumor activity was defined by NCI standards: median tumor volume of treated mice over control mice (%) &amp;gt; 42% (inactive), ≤ 42% (active), and &amp;lt;10% (highly active). Results and Conclusions: ADAM9 was highly expressed in multiple tumor types. A majority of the tumor samples had medium to high levels of ADAM9 with 62% of non-small cell lung carcinoma (NSCLC), 65% of triple negative breast cancer (TNBC), 73% of gastric cancer, and 85% of pancreatic cancer samples having H- scores of 101 to 300. The remaining tumor samples had lower levels of ADAM9 expression (H-score 1 to 100) with only 1.2% of NSCLC samples being ADAM9-negative. Activity of IMGC936 was analyzed in PDX models derived from NSCLC, TNBC, pancreatic and gastric cancers. The range of ADAM9 expression was 27 to 226 by H-score, with 80% of the samples having H-scores above 101. A single dose of IMGC936 at 8.6 mg/kg was well tolerated. Across the tumor types tested, IMGC936 was active or highly active in 24 out of 35 models (69%) with complete regressions in 6 models (4 NSCLC, 2 TNBC). The 24 IMGC936 sensitive models had H-scores between 65 and 224. The 11 non-sensitive models had H-scores between 27 and 226. The data suggest that factors independent of ADAM9 expression contribute to model sensitivity toward IMGC936 and warrant further biomarker exploration. These studies demonstrate that ADAM9 is highly expressed in a large number of solid tumor indications and show that IMGC936 has activity against multiple solid tumor types with a wide range of clinically relevant ADAM9 levels. These data support the clinical evaluation of IMGC936 (NCT04622774). Citation Format: Olga Ab, Juniper A. Scribner, Kerstin Sinkevicius, Deryk Loo, Stuart W. Hicks, Krystal Watkins, Francine Z. Chen, Christopher Espelin, Marian Themeles, Ying Li, Chet Bohac, Patrick Zweidler McKay, Paul A. Moore, Callum M. Sloss, Ezio Bonvini, Eric H. Westin. IMGC936, an investigational ADAM9-targeting antibody drug conjugate, is active against patient-derived ADAM9-expressing xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1841.

Cirmtuzumab, an Anti-ROR1 Antibody, in Combination with Ibrutinib: Clinical Activity in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) from a Phase 1/2 Study

Cirmtuzumab, an Anti-ROR1 Antibody, in Combination with Ibrutinib: Clinical Activity in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) from a Phase 1/2 Study

D101 EFFICACY OF LIGELIZUMAB IN PATIENTS WITH CHRONIC SPONTANEOUS URTICARIA INADEQUATELY CONTROLLED WITH OMALIZUMAB

In the Phase 2b core study, ligelizumab, a next generation high-affinity humanized monoclonal anti-IgE antibody, was effective in patients with chronic spontaneous urticaria (CSU) inadequately controlled by H1-antihistamines. This analysis evaluates the response to ligelizumab, during the Phase 2b extension study, in patients who did not achieve complete urticaria control with omalizumab in the core study.

Protein tyrosine phosphatase 1B as a therapeutic target for Graves' orbitopathy in an in vitro model.

Graves’ orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1β, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-β stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1β, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1β-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-β-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.