Human IgG1 mAb Research Articles

Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Results from the phase 1/2 TROPION-PanTumor02 study.

8548 Background: Dato-DXd consists of a humanized anti-TROP2 IgG1 mAb conjugated to a potent topoisomerase I inhibitor via a stable cleavable linker. In the Phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel in pts with previously treated, locally advanced or metastatic NSCLC (Ahn et al, ESMO 2023). The Phase 1/2, multicenter, open-label, multiple cohort TROPION-PanTumor02 study (NCT05460273) was designed to assess Dato-DXd in Chinese pts with advanced or metastatic solid tumors. Here we present results from the NSCLC cohort. Methods: Chinese pts (aged ≥18 years) with locally advanced or metastatic NSCLC with or without actionable genomic alterations (AGAs), who had been previously treated with immunotherapy and platinum-based chemotherapy (pts without AGAs) or targeted therapy and platinum-based chemotherapy (pts with AGAs), were enrolled. Pts received Dato-DXd (6 mg/kg IV Q3W). The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR) per RECIST v1.1. Analyses presented are based on the primary analysis data cut-off (DCO; Oct 9, 2023) with 6 months (mos) follow-up post the last pt’s first dose. Results: In the NSCLC cohort, 40 pts from 11 sites in China were enrolled. Median age was 59 years (range 33–74); 29 pts (72.5%) were male, and 18 (45.0%) were current or former smokers. 23 (57.5%)/17 (42.5%) pts had tumors with non-squamous/squamous histology. 5 pts (12.5%) had NSCLC with AGAs; 4 of these pts had sensitizing EGFR mutations. At DCO, 8 pts were ongoing treatment; median study follow-up was 8.1 mos (range 1.1–11.9). Overall, confirmed ORR by ICR was 45.0% (all partial responses), disease control rate by ICR was 85.0%, median duration of confirmed response was 8.3 mos, and median time to onset of response from first dose was 1.4 mos. ORR by ICR was 56.5% (13/23) in the non-squamous subgroup, 29.4% (5/17) in the squamous subgroup, and 75.0% (3/4) in pts with EGFR mutations. Median PFS by ICR (95% CI) was 7.4 mos (5.7–not calculable [NC]) overall, 9.6 mos (7.1–NC) in the non-squamous subgroup, and 5.5 mos (1.4–NC) in the squamous subgroup. Median treatment duration was 5.6 mos (range 0.7–10.6). Treatment-emergent adverse events (TEAEs) occurred in 95.0% of pts; grade ≥3 TEAEs occurred in 57.5%, and there were no fatal TEAEs. The most common TEAEs were nausea (62.5%), stomatitis (57.5%) and anemia (57.5%). TEAEs led to dose reduction/discontinuation in 20.0%/10.0% of pts. No adjudicated drug-related interstitial lung disease was reported. Conclusions: Dato-DXd showed encouraging efficacy in Chinese pts with advanced or metastatic NSCLC; the non-squamous subgroup appeared to derive the most benefit. The efficacy/safety profile was consistent with previous studies, with no new safety signals observed. Clinical trial information: NCT05460273 .

Phase 1 study of anti–immunoglobulin-like transcript 3 (ILT3) monoclonal antibody (mAb) MK-0482 + pembrolizumab (pembro) in patients with recurrent inoperable glioblastoma (GBM).

2046 Background: For patients with GBM, treatment options are limited once the disease has recurred and become inoperable after standard first-line therapy. ILT3 is an inhibitory receptor expressed on monocytic myeloid cells, including tolerogenic dendritic cells and myeloid-derived suppressor cells (MDSCs). High expression of ILT3 on these immune cells has been associated with immune tolerance and suppression of T-cell function. Data have shown that GBMs have high ILT3 expression and high levels of MDSCs within the tumor microenvironment (TME). MK-0482 is a novel humanized IgG4 mAb targeting ILT3. Inhibition of ILT3 with MK-0482 may help relieve immunosuppression and improve T-cell function within the TME. In the expansion cohort of the first-in-human phase 1 study (MK-0482-001; NCT03918278), MK-0482 was evaluated in combination with pembro in a cohort of patients with recurrent inoperable GBM. The safety and efficacy data from this cohort are presented herein. Methods: Patients aged ≥18 y with their first recurrent inoperable GBM and a Karnofsky performance status (KPS) ≥80 were enrolled. Patients received MK-0482 750 mg Q3W + pembro 200 mg Q3W IV for up to a maximum of 35 cycles. The primary objective was to determine safety and tolerability of MK-0482 + pembro. Secondary objectives were to evaluate ORR, DCR (CR + PR + SD), and DOR by investigator assessment per Response Assessment in Neuro-Oncology (RANO). Exploratory objectives included evaluation of PFS per RANO and OS. Results: Overall, 25 patients were enrolled and received study treatment. At data cutoff (October 3, 2023), median follow-up duration was 9.3 mo (range, 5.6-14.5); treatment was ongoing in 1 patient. Median age was 56 y (range, 33-76). Most patients were male (72%), had a KPS of 80 (68%), and had IDH1 wild-type tumors (88%). All patients had previously received systemic therapy: 24 of 25 (96%) received prior temozolomide and 3 of 25 (12%) received prior glasdegib. Overall, 22 patients (88%) had an adverse event (AE); 10 patients (40%) had treatment-related AEs, most commonly (≥10%) arthralgia (12%), fatigue (12%), and increased ALT (12%). Grade 3 treatment-related AEs occurred in 2 patients (8%; increased ALT [n = 1] and fatigue [n = 1]). No grade 4 or 5 treatment-related AEs occurred. Four patients (16%) experienced immune-mediated AEs (hypothyroidism, n = 2; hepatitis, n = 1; pancreatitis, n = 1); all were grade 1 or 2. Confirmed ORR was 12% (3/25; 95% CI, 2.5-31.2), DCR was 32% (8/25; 14.9-53.5), and median DOR was 11.1 mo (range, 9.9-16.6+). Median PFS was 1.4 mo (95% CI, 1.3-2.9) and median OS was 9.3 mo (6.3-13.7); 6-/12-mo PFS and OS rates were 24%/16% and 72%/36%, respectively. Biomarker data will be included in the presentation. Conclusions: MK-0482 + pembro had a manageable AE profile with modest antitumor activity in patients with recurrent inoperable GBM. Clinical trial information: NCT03918278 .

GEMINI-Gastric: A phase 2 study of novel treatment combinations in patients with locally advanced unresectable or metastatic gastric cancers.

TPS4182 Background: A large proportion of patients (pts) with gastric cancer present with locally advanced or metastatic disease, which is linked with poor survival. Platinum- and fluoropyrimidine-based doublet chemotherapy (CTx) remains the standard of care in advanced gastric cancers. Based on recent clinical data, immuno-oncology (IO) agents plus CTx can improve overall survival (OS) in pts with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have human epidermal growth factor receptor 2 negative/low expression (HER2–) and have not been previously treated for advanced/metastatic disease. GEMINI-Gastric (NCT05702229) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of multiple novel IO + CTx combination therapies in this setting. Methods: Adults (≥18 years) with previously untreated HER2– locally advanced unresectable, or metastatic gastric or GEJ adenocarcinoma are eligible. Pts should have measurable target disease per RECIST v1.1 and an ECOG performance status of 0–1. The GEMINI-Gastric design allows assessment of multiple novel agents plus CTx in different substudies (Table). Novel agents include: volrustomig, an anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody (mAb); rilvegostomig, an anti-PD-1/TIGIT bispecific humanized IgG1 mAb; AZD0901, a claudin18.2-targeted antibody-drug conjugate; and AZD7789, an anti-PD-1/TIM-3 bispecific mAb. Co-primary endpoints are objective response rate and progression-free survival (PFS) at 6 months by investigator assessment per RECIST v1.1. Secondary endpoints include safety, duration of response, PFS, OS, PK, and immunogenicity. Sample sizes have been selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Europe, and Asia. Clinical trial information: NCT05702229 . [Table: see text]

A phase I dose escalation trial of BCD-145 in patients with unresectable or metastatic melanoma.

9526 Background: BCD-145 (nurulimab) is a fully human IgG1 mAb with modified Fc-fragment (the 1st Gln is replaced by Glu in the heavy chain sequence, and there is no terminal dipeptide composed by Gly and Lys residues) that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction between CTLA-4 and its ligands. This allows to stimulate T-cell proliferation, cytokine production and induces antitumor immune response. Here we present the results of multicenter open-label single-arm multi-cohort phase I trial of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of BCD-145 in pts with unresectable/metastatic melanoma (unr/mM). Methods: BCD-145 monotherapy in 3+3 dose escalation [0.1, 0.3, 1, 3, 10 mg/kg intravenously Q3W] was given to 15 pts with unr/mM with measurable disease, who had failed prior therapy, ECOG 0-2. Pts with brain mts, previous therapy with aCTLA-4 and/or aPD-1/PD-L1 drugs were not allowed. The main objective of the study was to evaluate PK, PD, tolerability, immunogenicity, safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) identification. Secondary objectives included tumor response rate (irRECIST). Results: BCD-145 proved safety and overall was well tolerated. DLT and MTD were not reached. Any grade (Gr) adverse events (AEs) occurred in 100% (15/15) of pts. 33.3% (5/15) of pts had AE/SAE of Gr 3-4, including hypertension Gr 3 (1 at 1 mg/kg), hypercalcemia Gr 4 (2 at 1 mg/kg), hypokalemia Gr 3 (2 at 1 mg/kg), neutropenia Gr 3 (1 at 0.3 mg/kg), anemia Gr 3 (1 at 1 mg/kg), lung infection Gr 3 with hospitalization (1 at 1 mg/kg). Only 2 pts had a treatment-related AE Gr 3-4. Immuno-related AE were identified in 46.7% (7/15), manifested by symptoms of thyroiditis (mainly Gr 1) and diarrhea Gr 2 (1 at 10 mg/kg). There was 1 death (at 1 mg/kg) due to progression. There is dose-dependent peak study drug serum concentrations and systemic exposure. Two dosage regimens (1 mg/kg, 3 mg/kg Q3W) allowed to achieve the optimal concentration. BCD-145 increased subpopulations of activated HLA-DR+ CD4+ and CD8+ T lymphocytes, CD4+ICOS+ T-lymphocytes, absolute lymphocyte counts in all cohorts without significant differences. Binding and neutralizing Abs against BCD-145 were detected in 2 pts from different dose cohorts (0.3 mg/kg, 1 mg/kg). PR and SD were registered in 2 pts of each response group. 30.8% of pts achieved disease control, which is consistent with published data on other CTLA-4 inhibitors. A dose of 1 mg/kg is determined as recommended phase 2 dose (RP2D). Conclusions: BCD-145 demonstrated a tolerable safety profile and preliminary anti-tumor activity in pts with unr/mM. Anti-tumor effects of BCD-145 were observed in pts who had progressed on prior treatment. Further co-targeting PD-1 and CTLA-4 simultaneously will achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Clinical trial information: NCT03472027 .

GEMINI-Hepatobiliary: A phase 2 study of novel first-line immuno-oncology-based treatments in patients with advanced hepatobiliary cancers.

TPS4187 Background: Although targeted therapies and immuno-oncology (IO)-based regimens have improved overall survival (OS) in advanced hepatobiliary carcinomas, long-term survival rates remain unsatisfactory. Early-phase studies have demonstrated the efficacy of volrustomig (volru; anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody [mAb]) in patients (pts) with non-small-cell lung cancer (NSCLC) and renal cell carcinoma, and of rilvegostomig (rilve; anti-PD-1/TIGIT bispecific humanized IgG1 mAb) in pts with NSCLC, along with manageable safety profiles. GEMINI-Hepatobiliary (NCT05775159) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to evaluate the preliminary efficacy and safety of novel IO bispecific mAbs as monotherapy or in combination with standard of care anticancer agents in pts with advanced hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). Methods: The GEMINI-Hepatobiliary platform design permits separate independent substudies (Table). Substudy 1 includes treatment-naïve adults (≥18 years) with histologically confirmed advanced HCC not eligible for locoregional therapy, Barcelona Clinic Liver Cancer Stage B/C, Child-Pugh class A 5–6, and an ECOG performance status (PS) of 0–1. Pts will be treated with volru as monotherapy or in combination with bevacizumab or lenvatinib. Primary endpoints for Substudy 1 are safety and objective response rate (ORR) per RECIST v1.1 by investigator’s assessment. Substudy 2 includes treatment-naïve adults with locally advanced or metastatic, histologically confirmed BTC and an ECOG PS of 0–1. Pts will be treated with gemcitabine + cisplatin with either rilve or volru. Primary endpoints for Substudy 2 are safety and progression-free survival (PFS) per RECIST v1.1 by investigator’s assessment. Secondary endpoints for both substudies include duration of response, disease control rate, ORR, PFS, OS, pharmacokinetics, and immunogenicity. While there are no formal statistical comparisons or hypothesis testing, sample sizes were selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Asia, and Europe. GEMINI-Hepatobiliary master protocol design. Clinical trial information: NCT05775159 . [Table: see text]

Abstract CT132: A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors

Abstract Introduction: TST001/osemitamab is a novel, recombinant humanized IgG1 mAb with improved CLDN18.2 binding affinity and enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and can result in more efficient cytotoxicity of tumors expressing human CLDN18.2 across a broad range of levels including low to medium expression. Methods: This is an open-label, multi-center phase I/IIa first in human (FIH) study of osemitamab administered as monotherapy or in combination with nivolumab or standard of care for patients with locally advanced or metastatic solid tumors. The study includes two parts: Part A (completed), a dose escalation of osemitamab as a monotherapy in solid tumors, osemitamab intravenous infusion at dose from 1mg/kg to 10mg/kg and once every two weeks (Q2W) or once every three weeks (Q3W) were evaluated; Part B (ongoing) includes expansion cohorts of osemitamab in combination with other therapies (cohort A and B). Cohort A includes combination of osemitamab, nivolumab, and mFOLFOX6 as the 1st line treatment for G/GEJ cancer. Cohort B includes osemitamab in combination with nivolumab in advanced pre-treated G/GEJ cancer. Results: As of Nov. 30, 2023, 68 patients have been treated: 38 patients were enrolled in the Part A dose escalation,13 in Part B Cohort A, and 17 in Part B Cohort B. The population (N=68) consisted of 59% males, median age 62 years and 50% with G/GEJ cancer. Doses evaluated are 3 to 10mg/kg Q3W and 1 to 6 mg/kg Q2W in part A. One dose limiting toxicity of Grade 3 infusion related reaction was reported at the 1mg/kg dose Q2W. The MTD was not reached. The recommended phase 2 dose was determined as 6mg/kg Q3W or 4mg/kg Q2W based on the totality of available safety, efficacy, PK/PD data including information from another phase I/II study (TranStar102). The most common TRAEs (occurred in ≥ 20% subjects) were nausea (73.5%), vomiting (48.5%), fatigue (30.9%). TRAE of Grade ≥ 3 across all tested doses (3-10 mg/kg) that occurred in ≥3% of patients included nausea, vomiting, hypoalbuminemia, hypertension, infusion related reaction, and lymphocyte count increased. Within the dose ranges studied, PK exposures increased as dose increased. The mean CLss value of osemitamab ranged from 9.4 to 13.7 mL/day/kg across different dose levels, without a clear dose relationship. Mild accumulation was observed following Q2W and Q3W dosing. Conclusion: Osemitamab as monotherapy or in combination with nivolumab or mFOLFOX plus nivolumab is well tolerated and safe with a PK profile consistent with other studies (TranStar 102 study -NCT04495296). TranStar 101 is currently ongoing. More information will be shared. Clinical trial information: NCT04396821. Study Sponsor: Suzhou Transcenta Therapeutics Co., Ltd. Citation Format: Yelena Janjigian, Anthony Tolcher, Rutika Mehta, Michael Cecchini, Brian Van Tine, Madappa Kundranda, Alese Olatunji, Manish R. Patel, Jordan Berlin, Caio Max Sao Pedro Rocha-Lima, Dulabh Monga, Ben George, Aaron Scott, Zhenzhong Xia, Mohamed Elsafy, Erikca Jones, Zhenling Yao, Chuan Qi, Caroline Germa, Nash Gabrail. A Phase I/IIa clinical trial (TranStar101) to evaluate the safety, tolerability and pharmacokinetics of OSEMITAMAB administered as monotherapy or in combination with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT132.

Abstract 2716: The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs)

Abstract Introduction:NEO-201 is a humanized IgG1 mAb that targets Core 1 and/or extended Core 1 O-glycans expressed by several human solid and blood tumors, as well as neutrophils, but it does not bind to most normal tissues and human immune cell subsets (B cells, CD4+ T cells, CD8+ T cells, NK cells, monocytes). Functional analysis revealed that NEO-201 mediates the killing of its target cells through ADCC and CDC. Previous study has shown that approximately 4.6% of CD4+ T cells express NEO-201 target antigen and that those CD4+ T cells have Tregs phenotype. In addition, in a recent published phase 1 study we observed that NEO-201 binds to CD4+/CD25+/, CD127−/, Foxp3+/, CD15s+ cells from peripheral blood mononuclear cells (PBMCs) from cancer patients with solid tumors. The purpose of this study was to further characterize the phenotype of the specific subset of CD4+ T cells expressing the NEO-201 target antigen. Experimental Design: Human PBMCs were obtained from 7 healthy donors (HD) collected at Osaka University and 6 cancer patients from our ongoing phase II clinical trial (Clinical Trial NCT03476681) evaluating the efficiency of the combination of NEO-201 with pembrolizumab in adults with solid tumors resistant to checkpoint inhibitors. Phenotypic analysis was performed by flow cytometry using NEO-201 and antibodies CD3, CD4, CD25, CD45RA, FoxP3, and CD15s. The same gating strategy was applied for both normal donors and patients to evaluate which fraction of CD4+ T cells is recognized by NEO-201. Fraction (Fr) 1 is naïve Treg, Fr ll is effector Treg, Fr lll is non-Treg, Fr lV is effector CD4 T cells and Fr V is naïve CD4 T cells. Results: Flow cytometry analysis of PBMCs revealed that NEO-201 recognizes naïve Tregs (nTregs: CD3+/CD4+/CD45RA+/Foxp3low cells) while it does not bind to effector Tregs (eTregs: CD3+/CD4+/CD45RA−/Foxp3high cells) in both HD and cancer patients. The % of nTregs in cancer patients was higher than HD. Preliminary results from the ongoing Phase II clinical trial showed that subjects with durable SD had a reduction of circulating nTregs after treatment with NEO-201 compared to baseline levels. Conclusions: NEO-201 binds to human Tregs with significantly higher % of binding to Fr l and a greater % of Tregs expressing NEO-201 target antigen in cancer patients compared to HD. It is conceivable that naïve Tregs in cancer patients express high levels of Core 1 O-glycans. Furthermore, when subjected to TCR stimulation, naïve Tregs undergo proliferation and differentiate into eTregs. eTregs can then infiltrate into tumor microenvironment (TME). These data suggest that depletion of circulating nTregs in cancer patients after NEO-201 treatment may prevent the differentiation of nTregs into eTregs and their accumulation in the TME. This study suggests the potential use of NEO-201 to reduce the Treg-mediated suppression of anticancer immunity. Citation Format: Atsushi Tanaka, Massimo Fantini, Philip M. Arlen, Christina M. Annunziata, Kwong Y. Tsang, Shimon Sakaguchi. The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2716.

P165 Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling

Abstract Background IL-23 is implicated in the pathogenesis of inflammatory bowel disease (IBD) and myeloid cells that express FcγRI (CD64) have been identified as the primary cellular source of IL-23 in inflamed IBD gut tissue. Guselkumab (GUS) and risankizumab (RZB) are monoclonal antibodies (mAbs) specifically directed against the IL-23p19 subunit. GUS is a fully human IgG1 mAb with a native Fc region while RZB is a humanized IgG1 mAb with a mutated Fc region. Here, we evaluated CD64 and IL-23 expression in IBD patient gut biopsies, binding of GUS and RZB to CD64, and the functional consequences of CD64 binding by IL-23p19 subunit mAbs, in in vitro assays. Methods IL23A and FCGR1A (CD64) expression was analyzed from bulk and single-cell RNAseq datasets. Binding of mAbs to IFNγ-primed human monocytes, as well as binding to IL-23–secreting inflammatory monocytes and capture of endogenously secreted IL-23, were assessed by flow cytometry. Internalization of IL-23, GUS, and RZB within CD64+ macrophages was evaluated using live cell confocal imaging. Potency of GUS and RZB for inhibiting IL-23 signaling was determined in a co-culture of THP-1 (a CD64+ monocyte cell line activated to produce IL-23) and an IL-23 reporter cell line (measuring biologically active IL-23). Results Analysis of RNAseq datasets showed that FCGR1A, IL23A, and IL12B were significantly increased in inflamed versus non-inflamed IBD gut biopsies and that IL23A was predominantly expressed by FCGR1A-expressing myeloid cells. In in vitro assays GUS, but not RZB, showed Fc-mediated binding to CD64 on IFNγ-primed monocytes. CD64-bound GUS simultaneously captured IL-23 secreted from the same cells. GUS, but not RZB, bound to the surface of CD64+ macrophages and mediated internalization of IL-23 to low pH intracellular compartments. GUS and RZB demonstrated similar potency for inhibiting signaling by IL-23 present in THP-1–conditioned media. However, in a co-culture of IL-23–producing THP-1 cells with an IL-23–responsive reporter cell line, GUS demonstrated enhanced potency compared to RZB for inhibition of IL-23 signaling. Conclusion Our transcriptomic analysis supported previous observations of CD64+ myeloid cells as a key source of IL-23 production in inflamed IBD gut tissue. GUS binding to CD64 on IL-23–producing cells likely contributed to the enhanced functional potency of GUS compared to RZB for inhibition of IL-23 signaling in the co-culture assay. These in vitro data support a hypothesis for optimal enrichment of GUS in inflamed tissues where CD64+ IL-23–producing myeloid cells are increased and in proximity to IL-23–responsive lymphoid cells, enabling GUS to more potently neutralize IL-23 by targeting IL-23 at its source of production.

Abstract C069: Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status

Abstract Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have revolutionized cancer treatment favoring prognostic benefits to a broad range of cancer patients. Currently, US Food and Drug Administration (FDA)–approved PD-1 monoclonal antibodies (mAbs) have demonstrated significant clinical benefit, particularly in patients with programmed cell death ligand 1 (PD-L1)-expressing tumors. Toripalimab is a PD-1 targeting humanized IgG4 mAb that is currently pending approval by the FDA as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In combination with chemotherapy, toripalimab demonstrated significant clinical efficacy irrespective of PD-L1 status in patients in three different clinical trials, namely JUPITER-02 (NPC), JUPITER-06 (esophageal squamous cell carcinoma [ESCC]) and CHOICE-01 (non-small cell lung cancer [NSCLC]). Here we investigated the molecular and functional characteristics of toripalimab and compared it to pembrolizumab, a PD-1 mAb that is approved in the largest number of indications in the PD-1 mAb class. In comparison to pembrolizumab, toripalimab demonstrated a 12-fold higher binding affinity to PD-1 and selectively induced higher Th1 and myeloid derived inflammatory cytokine responses in human peripheral blood mononuclear cells (PBMCs). Upon treating dissociated tumor cells from treatment naïve NSCLC patients, toripalimab demonstrated an enhanced expression of several unique genes in interferon gamma and immune cell pathways compared to pembrolizumab. The binding of toripalimab to PD-1 ectopically expressed in Jurkat T cells, recruited lower levels of SHP1 and SHP2, the negative regulators of T cell activation, compared to pembrolizumab. Overall, our study demonstrates that toripalimab is differentiated from pembrolizumab in terms of stronger PD-1 binding, more potent in-vitro T cell activation and lower agonistic potential. These characteristics of toripalimab present it as a next generation PD-1 checkpoint inhibitor with potential for favorable clinical outcomes in treating cancer patients irrespective of their PD-L1 status. Citation Format: Xiaoguang Wang, Sruthi Ravindranathan, Daniel Chin, Su-Yi Tseng, Scott Klakamp, Kate Widmann, Varun Kapoor, Vladimir Vexler, Patricia Keegan, Sheng Yao, Sanjay D Khare, Theresa LaVallee, Narendiran Rajasekaran. Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C069.

1363. Preliminary Safety Results from a Phase 1 First in Human Study of VYD222: an Extended Half-Life Monoclonal Antibody (mAb) in Development for COVID-19 Prevention

Abstract Background VYD222 is a fully human IgG1 mAb demonstrating broad and potent in vitro neutralizing activity across SARS-CoV-2 variants including XBB.1.5. VYD222 is a re-engineered version of adintrevimab, an Fc-modified mAb that has a robust safety data package and demonstrated clinically meaningful results in Phase 2/3 clinical trials for both treatment and prevention of COVID-19 (NCT04805671, NCT04859517). VYD222 is currently in development for COVID-19 prevention. Methods This is an ongoing Phase 1, first in human, blinded, randomized, placebo (PBO)-controlled, single ascending dose study of VYD222 administered as slow intravenous (IV) push to healthy adults aged 18-65 years (NCT05791318). Participants were randomized 8:2 in each of 3 cohorts (n=8 VYD222, n=2 PBO): VYD222 1500 mg, 2500 mg, and 4500 mg. Safety and tolerability will be assessed as incidence of treatment emergent adverse events, including serious adverse events (SAEs). Serum pharmacokinetic (PK) parameters will be calculated for VYD222 using noncompartmental analysis methods. Serum virus neutralizing antibody (sVNA) titers of VYD222 ex vivo against relevant SARS-CoV-2 variants will be assessed using a validated assay. Safety, tolerability, PK, and sVNA titers will be assessed through 12 months post-dose. Here we report preliminary blinded safety results from cohorts 1 and 2. Results Overall, 12 participants received VYD222 or PBO. Through a minimum of 14 days post dose, among 10 participants in cohort 1 (VYD222 1500 mg n=8, PBO n=2), there were 9 AEs (adverse events) reported, all of which were mild in severity and considered unrelated to study drug. No participant experienced SAEs, infusion-related reactions, or hypersensitivity reactions. Through 2 days post dose, 2 sentinel participants in cohort 2 (VYD222 2500 mg n=1, PBO n=1) experienced zero AEs, study drug related AEs, SAEs, infusion-related reactions, or hypersensitivity reactions. Enrollment continues in cohort 2 as of the data cutoff (04/25/2023) for this abstract. Data remain blinded currently. Conclusion To date, a single dose of VYD222, up to 2500 mg IV push, was well tolerated across all healthy participants receiving either VYD222 or PBO in this ongoing phase 1 study. These findings support continued clinical development of VYD222. Disclosures Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Natalia Betancourt, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Aanika Das, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Ed Campanaro, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Pete Schmidt, MD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds

Dual Targeting of Slamf-7 and CD38 in Mulitple Myeloma (MM): A Phase II Study of Isatuximab, Elotuzumab, Pomalidomide and Dexamethasone (Isa-EloPD) in Relapsed and/or Refractory MM (RRMM)

Background: Elotuzumab (Elo) is a humanized IgG1 mAb that targets SLAMF7, an antigen highly expressed on malignant plasma cells. Isatuximab (Isa) is a humanized IgG1 mAb that binds to the unique CD38 epitope present on MM cells. Both mAbs have independently shown to be safe and effective when combined with pomalidomide and dexamethasone (PD) in patients with RRMM. Dual targeting of CD38 and SLAMF7 could be synergistic as the simultaneous expression of both antigens has been identified in 97% of primary MM cells, even among heavily treated patients (PMID 33420283). Further evaluation is necessary to assess the anticipated decline in lymphocyte subsets, particularly NK cells (express CD38 and SLAMF7), resulting from the combination. Here we report the safety and preliminary activity of the first ever combination of Isa, Elo, PD in patients with RRMM (IMPEDE-NCT04835129). Methods: This is a single arm, multi-center, phase II study with safety lead-in in patients with RRMM with 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) and refractory to the last line of therapy. Patients with prior Elo and pomalidomide are excluded while prior anti-CD38 mAb is permitted with adequate washout and non-refractory status. A safety run-in phase was performed in 6 patients to assess for potential dose limiting toxicities (DLTs). Isa-EloPD was given on a 28-day cycle, and Elo was given per the EloPD schedule. To allow proper correlative assays informing the impact of Isa and Elo on lymphocyte subpopulations, Isa was sequentially introduced after Elo-PD in the safety run-in on cycle 2. For the first dose, Isa was given on day 2 after Elo and the same day subsequently. Treatment was given until progression or unacceptable toxicity occurred. The primary end point was overall response rate (ORR). Secondary end points included overall safety, duration of response, progression free (PFS) and overall survival (OS). Correlative analyses included changes in lymphocyte sub-populations and NK cell cytolysis for the first 2 cycles in the safety lead in phase. For NK cell cytolysis, PBMCs from individual patients were co-cultured with K562 target cells at serial effector: target (E: T) cell ratios. Peak cytolysis during the first 24 hours represents NK cell-mediated cytolysis. Based on Simon's two-stage design, a total accrual of 53 patients is planned. Results: At the time of data cut-off, 15 patients were enrolled. Median age was 68 years (range, 54-79) and 3 were African American. Disease was refractory to lenalidomide in all patients, and refractory to both bortezomib and lenalidomide in 3 patients. Six patients were previously exposed to anti-CD38 mAb. Eleven (73%) patients had presence of high-risk cytogenetics including del 17p, t (4;14), t (14;16) and 1q gain/amp. All 6 patients in in the safety lead-in cohort completed at least 2 cycles of treatment (DLT window), while the remaining patients completed at least 1 cycle of treatment. The median follow up was 8.5 months (1-16.6). None of the patients experienced DLT in the safety lead-in phase. Grade 3-4 treatment emergent adverse events (TEAEs) occurred in 15 (100%) of patients with most common being lymphopenia (93%), neutropenia (93%) and leucopenia (40%). Grade 3-4 infections occurred in 1(7%) patient. No grade 5 TEAEs occurred. Infusion related reactions occurred in 1 patient, maximum grade 2. All patients were evaluable for response with an ORR of 80% (12/15) (6 VGPR or better, 6 PR), and 100% in anti-CD38 mAb naive. The 12-month PFS rate was 67% (45%-99%). 5 patients discontinued the study (4 due to disease progression and 1 withdrew consent). Lymphocyte subpopulations showed a decrease in relative and absolute NK cells and an increase in monocytes (Figure 1 A, B). NK cell cytolytic activity was maintained in patient samples obtained over the course of the study (Figure 1C). Conclusions: This is the first ever report combining two different mAbs with dual targeting of CD38 and SLAMF7 in RRMM. The results demonstrate that Isa-EloPD combination is both safe and feasible with high frequency and durability of responses. Despite an anticipated reduction in number, NK cell cytotoxicity remain unaffected with the combination. The study is ongoing and results from additional patients and longer follow up will be presented.

Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non-Small Cell Lung Cancer.

Overexpression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been reported in several tumor types, including non-small cell lung cancer (NSCLC), and has been shown to promote tumor-immune evasion and inhibit T-cell activation through increased tryptophan degradation and the production of several immunosuppressive metabolites collectively known as kynurenines. However, it remains unclear whether IDO1 expression by tumor cells is detrimental specifically in the context of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis blockade. We analyzed the transcriptome of 891 NSCLC tumor samples from patients enrolled in two large randomized clinical trials investigating the safety and activity of atezolizumab, a humanized IgG1 mAb that targets PD-L1, versus docetaxel in patients with advanced NSCLC. We complemented these transcriptomics results at the protein level by using multiplex immunofluorescence and at the functional level with in vitro experiments. The increased expression of the tryptophan-catabolizing enzyme IDO1 was significantly associated with improved objective response, progression-free survival, and overall survival in patients treated with PD-L1 inhibitors, but not in those treated with chemotherapy. Strikingly, inflamed tumors had higher levels of IDO1, and IDO1 was also expressed in tertiary lymphoid structures (TLS) by mature follicular dendritic cells. L-kynurenine impaired the differentiation of antibody-producing B cells induced by follicular helper T (Tfh)/B-cell interactions, a hallmark process within TLS. IDO1 pathway in NSCLC is driven by the immune system rather than by tumor cells. Targeting IDO1 in combination with anti-PD-1/PD-L1 might be beneficial only in patients with inflamed tumors and particularly in those bearing TLS.

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1andPD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways mayprovide additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

Phase II study combining an anti-core 1 O-glycans targeting humanized monoclonal antibody NEO-201 with pembrolizumab in adults with chemo-resistant solid tumors.

e14515 Background: NEO-201 is a humanized IgG1 mAb which binds to Core 1 and/or extended Core 1 O-glycans expressed by solid and hematological cancers. NEO-201 reacts against cancer tissues but not most normal tissues. NEO-201 can identify and kill immune suppressor cells (iSCs), such as regulatory T cells (Tregs), neutrophils, and granulocytic myeloid-derived suppressor cells (gMDSCs) in human PBMCs via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). We observed a reduction in the percentage of circulating Tregs in subjects with stable disease (SD) following single-agent NEO-201 treatment in our Phase 1 study. Resistance to PD-1/PD-L1 blockade in solid cancers may be due to the activity of iSCs in the tumor microenvironment (TME). Based on this, we launched a Phase II study with a safety lead-in combining NEO-201 with pembrolizumab in adults who have progressed on prior checkpoint therapy. Methods: The recommended phase 2 dose (RP2D) of NEO-201 was determined to be 1.5 mg/kg IV every 2 weeks. Cohorts consisting of advanced non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), uterine or cervical cancer who progressed during or after one front-line standard of care treatment, including chemotherapy, checkpoint therapy and/or targeted therapy were eligible. Three patients received NEO-201 at the RP2D with pembrolizumab 400 mg IV every 6 weeks (1 cycle) and were evaluated for safety 2 weeks following the 1st cycle of the therapy. DLTs were defined as specific Grade 3 or 4 toxicities related to NEO-201. Results: Safety lead-in was successfully completed at RP2D with no DLTs. Four subjects were enrolled in the safety lead-in; one subject electively discontinued after the first infusion and was not evaluable for DLT. Of the 3 evaluable subjects, 1 subject with refractory cervical cancer remained on study with SD for 8.5 months, electively coming off study for surgical debulking. The other 2 subjects developed progressive disease. All subjects had grade 3-4 transient neutropenia, which was expected. Other common toxicities included grade 3-4 decreased white blood cells and lymphocytes, grade 3 anemia and grade 2 infusion reactions. Conclusions: NEO-201 has demonstrated the ability to bind and kill iSCs in vitro and this phenomenon was observed in the initial first in human clinical study. This Phase II study was designed to determine if NEO-201 can reactivate the effectiveness of checkpoint inhibitor therapy in subjects who previously progressed on check point therapy. The safety of combining NEO-201 with pembrolizumab has been successfully established and all 4 disease cohorts are now open to accrual with response rate as the primary endpoint. The maximum accrual on this study will be 126 patients. Clinical trial information: NCT03476681 .

Long-term Efficacy and Safety of Symptom-driven Cyclic Rozanolixizumab Treatment in Patients with Generalized Myasthenia Gravis: A Pooled Analysis of a Phase 3 Study and Two Open-label Extension Studies (P1-5.012)

Long-term Efficacy and Safety of Symptom-driven Cyclic Rozanolixizumab Treatment in Patients with Generalized Myasthenia Gravis: A Pooled Analysis of a Phase 3 Study and Two Open-label Extension Studies (P1-5.012)

Abstract 5654: A therapeutic humanized anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human granulocytic myeloid-derived suppressor cells (gMDSCs) and regulatory T (Tregs) cells

Abstract Background: NEO-201 is a humanized IgG1 mAb reactive against multiple human cancers but not against most normal epithelial tissues. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells, including neutrophils, various carcinomas, and some human hematological malignancies. NEO-201 can mediate antitumor activity through antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and blockade of the CEACAM5/CEACAM1 ICI pathway. A previous study using flow cytometry demonstrated that NEO-201+/CD4+ T cells were also CD25+/CD127−/Foxp3+/CD15s+ using PBMCs from healthy donors (HD). NEO-201 can kill these Treg cells through CDC in vitro. NEO-201 does not bind to the majority of CD4+ T cells and to other immune subsets. Human gMDSCs are increased in cancer patients and are a population of immature MDSCs deriving from immature neutrophils and alternative activation of mature neutrophils. gMDSC are characterized by HLA-DR−, CD11b+, CD33+, CD15+phenotype.We have shown that NEO-201 recognizes and kill human neutrophils through ADCC. This current investigation was designed to evaluate whether NEO-201 can target and mediate ADCC activity against human gMDSCs. Methods: gMDSCs were generated from human neutrophils from 5 HD isolated using EasySepTM direct human neutrophil isolation kit. Isolated neutrophils were cultured in complete RPMI1640 medium supplemented with human GM-CSF and human IL-6 for 7 days. Phenotypic analysis by flow cytometry was performed on the generated gMDSCs using NEO-201 and mAbs against human CD33, HLA-DR, CD15, CD14, CD66b. Flow cytometry based ADCC assay was performed using gMDSCs stained with both CD33 and HLA-DR as target. PBMCs from a separate HD were used as effectors at different E:T ratios. The ADCC activity of NEO-201 was evaluated comparing the percentage of CD33+/HLA-DR− viable cells in gMDSCs incubated with medium alone to the percentage of CD33+/HLA-DR− viable cells incubated with PBMCs alone and with PBMCs plus NEO-201. Results: Flow cytometry analysis revealed that gMDSCs can be generated from human neutrophils after 7 days of culture with GM-CSF and IL-6 and that they express the following phenotype: HLA-DR−/CD33+/CD15+/CD14−/CD66b+. NEO-201 bound to the majority of these gMDSCs. NEO-201 was functional in mediating ADCC to kill these gMDSCs. Conclusion: This study demonstrated that NEO-201 can be used to identify and kill suppressive gMDSCs in addition to Treg cells. Depletion of suppressive Tregs and gMDSCs in the TME could be an effective strategy to prevent hyperprogressive disease when anti-PD-1 is used in cancer immunotherapy. These data support the rationale for the ongoing phase II clinical trial using NEO-201 in combination with pembrolizumab in checkpoint refractory patients with metastatic solid tumors. Citation Format: Massimo Fantini, Christina M. Annunziata, Philip M. Arlen, Kwong Y. Tsang. A therapeutic humanized anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human granulocytic myeloid-derived suppressor cells (gMDSCs) and regulatory T (Tregs) cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5654.

Abstract P6-10-03: Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 mAb covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor selective, tetrapeptide-based cleavable linker. Dato-DXd has previously shown encouraging activity in heavily pretreated patients (pts) with metastatic TNBC (Krop, SABCS 2021). Here we report updated results from the TROPION-PanTumor01 study in pts with advanced/metastatic TNBC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with advanced TNBC that relapsed/progressed on standard therapies; 2 pts received 8 mg/kg prior to selection of 6 mg/kg. The primary objectives were safety and tolerability. Tumor responses, including objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]), were assessed per RECIST v1.1 by blinded independent central review. Results: As of April 29, 2022, 44 pts received Dato-DXd (median follow-up, 16.6 mo [range, 13-22]) at the time of data cutoff. The primary cause of treatment discontinuation was disease progression (86%; PD or clinical progression), and 4 pts are still receiving therapy. Median age was 53 y (range, 32-82); 32% had de novo metastatic disease. Pts were heavily pretreated with a median of 3 (range, 1-10) prior regimens in the metastatic setting. Prior treatments included taxanes (91%), anthracyclines (75%), capecitabine (61%), platinum (52%), immunotherapy (43%), Topo I inhibitor–based ADC therapy (32%), and PARPi (18%). Treatment-emergent adverse events (TEAEs; all cause) occurred in 100% (any grade) and 50% (grade ≥3) of pts, respectively. Most common TEAEs (any grade, grade ≥3) were stomatitis (73%, 11%), nausea (66%, 2%), vomiting (39%, 5%), fatigue (34%, 7%), and alopecia (36%, 0%). One pt had grade 3 decreased neutrophil count; no cases of interstitial lung disease (ILD) or grade ≥3 diarrhea were observed. Serious TEAEs were reported in 9 pts (20%); no deaths associated with adverse events (AEs) were observed. Dose reductions occurred in 8 pts (18%) due to stomatitis (n=3), fatigue (n=2), dry eye (n=1), retinal exudates (n=1), and dysgeusia (n=1); 12 pts (27%) delayed treatment due to stomatitis (n=5), dry eye (n=1), keratitis (n=1), blurred vision (n=1), fatigue (n=1), bronchitis (n=1), skin infection (n=1), musculoskeletal chest pain (n=1), dysgeusia (n=1), chronic obstructive pulmonary disease (n=1), and dyspnea (n=1; >1 AE per pt). One pt (2%) discontinued treatment due to grade 1 pneumonitis (which was centrally adjudicated as not ILD). ORR in all pts was 32% (1 CR, 13 PRs), DCR was 80% (35/44), and clinical benefit rate (CR + PR + SD ≥6 mo) was 34% (15/44). Median duration of response was not yet reached; median progression-free survival (mPFS) was 4.3 mo (95% CI, 3.0-7.3), and median overall survival (mOS) was 12.9 mo (95% CI, 10.1-14.7). In the subset of pts without prior Topo I inhibitor–based ADC therapy and with measurable disease at baseline, ORR was 44% (12/27). Among all pts without prior Topo I inhibitor–based ADC therapy (n=30), mPFS was 7.3 mo (95% CI, 3.0-NE), and mOS was 14.3 mo (95% CI, 10.5-NE). Conclusions: Dato-DXd continues to demonstrate encouraging and durable antitumor activity, along with a manageable safety profile, in heavily pretreated pts with metastatic TNBC. Based on these findings, the phase 3 randomized TROPION-Breast02 (NCT05374512) trial comparing Dato-DXd vs chemotherapy as 1L therapy for pts with metastatic TNBC is currently underway. Citation Format: Aditya Bardia, Ian Krop, Funda Meric-Bernstam, Anthony W. Tolcher, Toru Mukohara, Aaron Lisberg, Toshio Shimizu, Erika Hamilton, Alexander I. Spira, Kyriakos P. Papadopoulos, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Takahiro Kogawa. Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-03.

Abstract OT1-03-04: Datopotamab deruxtecan (Dato-DXd), a TROP2 antibody-drug conjugate, vs investigators’ choice of chemotherapy in previously-treated, inoperable or metastatic HR+/HER2– breast cancer: TROPION-Breast01

Abstract Background: Chemotherapy is the main treatment in patients with pre-treated endocrine-resistant HR+/HER2– metastatic breast cancer, but has limited efficacy and substantial toxicities. The antibody-drug conjugate Dato-DXd consists of a humanized IgG1 mAb targeting TROP2 attached via a stable cleavable linker to a topoisomerase I (TopI) inhibitor payload. Heavily pre-treated patients with metastatic triple-negative breast cancer in the TROPION-PanTumor01 (NCT03401385) study of Dato-DXd showed a manageable safety profile and highly encouraging objective response rates (ORR by blinded independent central review [BICR]: 34% in all patients; 52% in patients treatment-naïve to TopI inhibitor-based therapies). The metastatic HR+/HER2– breast cancer cohort of TROPION-PanTumor01 has completed enrollment (n=41); data are currently maturing. Trial design: TROPION-Breast01 (NCT05104866) is an ongoing, global, phase 3, open-label, randomized trial evaluating efficacy and safety of Dato-DXd vs investigators’ choice of chemotherapy (ICC) in patients with inoperable or metastatic HR+/HER2– breast cancer. Patients (n≈700) are randomized 1:1 to Dato-DXd 6 mg/kg IV Q3W or ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) until progression. Adults with an ECOG performance status of 0–1, who experienced progression on or are unsuitable for endocrine therapy, and received 1–2 prior lines of standard-of-care chemotherapy in the inoperable or metastatic setting are eligible. Monotherapy treatment with inhibitors of mTOR, PD-[L]1, CDK4/6 and PARP do not count as prior chemotherapy lines. Patients must have ≥1 measurable lesion per RECIST 1.1 and an archival or fresh formalin-fixed and paraffin-embedded tumor sample. Clinically inactive brain metastases are permitted. Dual primary endpoints are progression-free survival (PFS) by BICR, and overall survival. Secondary endpoints include PFS per investigator, ORR, disease control rate, patient-reported outcomes, and Dato-DXd pharmacokinetics and immunogenicity. Exploratory endpoints include TROP2 expression and exposure–efficacy relationship. Patients are stratified by number of prior chemotherapy lines, prior CDK4/6 inhibitor use, and region. At the time of writing 236 patients have been enrolled across 19 countries. Citation Format: Aditya Bardia, Kevin Kalinsky, Junji Tsurutani, Erika Hamilton, Joo Hyuk Sohn, Kyong Hwa Park, Yeon Hee Park, Seock-Ah Im, Keun Seok Lee, Daisy Dastur, Vincent Haddad, Sabrina Khan, Binghe Xu, Barbara Pistilli, Hope Rugo. Datopotamab deruxtecan (Dato-DXd), a TROP2 antibody-drug conjugate, vs investigators’ choice of chemotherapy in previously-treated, inoperable or metastatic HR+/HER2– breast cancer: TROPION-Breast01 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-04.

Development of a novel capillary electrophoresis method for quantitative measurements of intracellular recombinant protein titer

The measurement of volumetric titer is an integral step in the assessment and selection of a production cell line and cell culture process. The production of monoclonal antibodies (mAbs), a major class of therapeutic proteins, in Chinese Hamster Ovary (CHO) cell lines is challenging due to the clone-to-clone variations in the intrinsic capability to secrete a biologically complex protein. The measurement of intracellular mAb concentration could be a valuable tool to determine the ratio of intracellular to secreted product and be part of the evaluation of potential mAb productive cell lines. High throughput automation is a valuable tool that is used in bioprocess development to reduce work intensive steps. When coupled with the Simple Western (Wes) platform, automated capillary electrophoresis is an efficient method to measure recombinant protein concentration. In this study, we demonstrate the utility of using the automated Wes to rapidly measure intracellular titer and then compare the intracellular titer, volumetric titer and specific productivity between high and low production CHO clones expressing a model human IgG1 mAb.

Antibody-based protection against respiratory syncytial virus in mice and their offspring through vectored immunoprophylaxis.

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, with potential lower respiratory tract infections, which can be particularly problematic in infants and the elderly. There are no approved vaccines for RSV. The current standard of care for high-risk individuals is monthly administration of palivizumab, a humanized murine monoclonal antibody (mAb) targeting the RSV fusion protein. Adeno-associated virus (AAV)-mediated expression of mAbs has previously led to sustained expression of therapeutic concentrations of mAbs in several animal models, representing an alternative to repetitive passive administration. Intramuscular (IM) administration of AAV6.2FF expressing RSV antibodies, palivizumab or hRSV90, resulted in high concentrations of human (h)IgG1 mAbs in the serum and at various mucosal surfaces, while intranasal administration limited hIgG expression to the respiratory tract. IM administration of AAV6.2FF-hRSV90 or AAV6.2FF-palivizumab in a murine model provided sterilizing immunity against challenge with RSV A2. Evidence of maternal passive transfer of vectorized hRSV90 was detected in both murine and ovine models, with circulating mAbs providing sterilizing immunity in mouse progeny. Finally, addition of a "kill switch" comprised of LoxP sites flanking the mAb genes resulted in diminished serum hIgG after AAV-DJ-mediated delivery of Cre recombinase to the same muscle group that was originally transduced with the AAV-mAb vector. The ability of this AAV-mAb system to mediate robust, sustained mAb expression for maternal transfer to progeny in murine and ovine models emphasizes the potential of this platform for use as an alternative prophylactic vaccine for protection against neonatal infections, particularly in high-risk infants.