Aptevo Therapeutics (United states)

BackgroundALG.APV-527 is a bispecific antibody targeting costimulatory receptor 4-1BB (CD137) and the oncofetal tumor-associated antigen 5T4. 5T4 is expressed by multiple solid tumor types, such as non-small cell lung cancer, breast cancer, pancreatic, and gastrointestinal cancers with minimal expression in normal tissue. 4-1BB is an activation-induced costimulatory receptor that regulates immune responses of activated tumor-specific CD8 T cells and natural killer cells. ALG.APV-527 is designed to deliver a 5T4-conditional 4-1BB–mediated antitumor activity and minimize systemic immune activation and toxicity. Preclinically, ALG.APV-527 demonstrates robust antitumor activity by inhibiting the growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response,1 providing a rationale for evaluating ALG.APV-527 in patients with advanced solid tumors with the possibility of combining with immune checkpoint inhibitors (ICI).MethodsThe Phase 1 study is a first-in-human, open-label, multicenter trial consisting of up to six cohorts (0.1–15 mg/kg) in a 3+3 dose escalation of ALG.APV-527 monotherapy, administered intravenously Q2W, in adult patients with advanced solid tumors. Eligibility is limited to patients with tumor types identified as likely to express 5T4. Key endpoints include safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamic activity and clinical antitumor activity of ALG.APV-527.ResultsALG.APV-527 has been well tolerated in 18 enrolled patients, including 2 patients enrolled in dose level 5 (12 mg/kg). Enrollment and assessment of dose level 5 is ongoing. Most treatment-emergent adverse events (TEAEs) were mild to moderate and manageable in the clinic; Grade 1 (G1): 31 (41%), G2: 33 (43%), G3: 9 (12%), G4: 3 (4%), G5: 0. One patient experienced a G4 dose limiting toxicity of febrile neutropenia. MTD has not been determined. Pharmacokinetics was favorable: Serum concentrations were consistent with administered doses. Exposure is associated with changes in pharmacodynamic biomarkers reflecting ALG.APV-527 mode of action. Expression of 5T4 and 4-1BB was detected in tumor biopsies. Two heavily pretreated breast cancer patients experienced prolonged stable disease (SD) of over 7 months and 12 months (the second of which escalated to a higher dose level twice without any added adverse events and remains on study).ConclusionsAvailable data for ALG. APV-527 treatment demonstrates good tolerability, safety, biological activity, and prolonged SD in some patients suggesting clinical benefit of treatment. Upon determining the optimized dose, subsequent development will likely take place as a combination treatment.ReferenceNelson MH, Fritzell S, Miller R, Werchau D, Van Citters D, Nilsson A, Misher L, Ljung L, Bader R, Deronic A, Chunyk AG, Schultz L, Varas LA, Rose N, Håkansson M, Gross J, Furebring C, Pavlik P, Sundstedt A, Veitonmäki N, Ramos HJ, Säll A, Dahlman A, Bienvenue D, von Schantz L, McMahan CJ, Askmyr M, Hernandez-Hoyos G, Ellmark P. The bispecific tumor antigen-conditional 4-1BB x 5T4 agonist, ALG.APV-527, mediates strong T cell activation and potent anti-tumor activity in preclinical studies. Mol Cancer Ther. 2022;22(1).

Abstract Mutations in the RAS family are highly prevalent in human cancers, including up to 35% of non-small cell lung, 45% of colorectal, and 95% of pancreatic cancers. Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated RAS oncogene and patients with KRAS mutations have poor responses to standard treatment regimens. Therefore, successful KRAS-targeted therapies represent a high unmet need. The AFNT-111 cellular therapy consists of autologous CD8+ and CD4+ T cells expressing a high affinity TCR specific for the prevalent KRASG12V mutation presented by HLA-A*11:01, one of the most common HLA alleles worldwide. AFNT-111 is engineered to express the CD8α/β coreceptor, enabling a coordinated CD4+/CD8+ tumor response to induce robust T cell activity and persistence while minimizing T cell exhaustion. Lentiviral vector was used to transduce primary healthy human CD4+ and CD8+ T cells with the KRASG12V-specific human TCR and CD8α/β coreceptor. Engineered T cells were assessed against exogenous KRASG12V peptide as well as a panel of tumor cell lines endogenously expressing KRASG12V and probed for in vitro activation, proliferation, cytotoxicity and cytokine secretion. In parallel, in vitro safety studies were performed to evaluate autoantigen cross-reactivity and alloreactivity. In vivo efficacy studies were conducted using established human KRASG12V xenografts in NSG mice. AFNT-111 demonstrated potent functional avidity towards the KRASG12V peptide with no reactivity against KRASWT. Several naturally expressing KRASG12V human tumor cell lines led to significant AFNT-111 T cell activation and proliferation, as well as potent cytotoxicity. The addition of the CD8α/β coreceptor revealed a coordinated and synergistic cytotoxic CD4+ and CD8+ T cell response, enhancing activation of the AFNT-111 cell product. Robust cytotoxicity was associated with increased T cell secretion of IFNγ and TNFα. Durable in vivo anti-tumor efficacy was observed in three established mouse xenograft tumor models. XScan studies using amino acid substitutions of the index KRASG12V peptide revealed a restrictive TCR recognition motif. Further, potentially cross-reactive human self-peptides matching this motif were tested and no significant cross-reactivities were identified. To test alloreactivity, a large lymphoblastoid cell line library was assessed with no alloreactive responses detected. A streamlined manufacturing process has also been developed in which CD4+/CD8+ T cell ratios are controlled, with the final AFNT-111 product retaining a high degree of stem-like properties. AFNT-111 preclinical data demonstrate a highly potent and specific TCR-engineered T cell product that is cytotoxic to KRASG12V-expressing tumor cells both in vitro and in vivo. Cross-reactivity and alloreactivity assessments establish a potentially favorable safety profile of AFNT-111, supporting clinical translation. First-in-human clinical studies will focus on advanced or metastatic pancreatic, colorectal, and lung cancer indications. Citation Format: Michele Hoffmann, Xingyue He, Cheryl Black, Joshua Francis, James Parsons, Christian Roy, Jinsheng Liang, Hongjing Qu, Martin Campbell, Tomasz Sewastianik, Jessica Webb, Aude Chapuis, Thomas Schmitt, Philip Greenberg, Damien Hallet, Markus Vallaster, Piotr Pierog, Gary Shapiro, Hubert Lam, Loic Vincent. AFNT-111: A novel TCR-engineered T cell therapy targeting the oncogenic driver KRAS G12V [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A009.

Simple SummaryAML is a common form of blood cancer in adults. This study was undertaken to evaluate if AML patients who have failed the available standard treatment options could tolerate and potentially benefit from a new form of therapy. This new therapy activates patients’ own immune system against AML cells. The findings from this research may provide the foundation for a potentially more effective future form of standard therapy that is less likely to fail.APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

BACKGROUND Behavioral mitigation strategies to slow the spread of COVID-19 have resulted in sweeping lifestyle changes, with short- and long-term psychological, well-being, and quality of life implications. The Attitudes About COVID-19 and Health (ATTACH) study focuses on understanding attitudes and beliefs while considering the impact on mental and physical health and the influence of broader demographic and geographic factors on attitudes, beliefs, and mental health burden. OBJECTIVE In this assessment of our first wave of data collection, we provide baseline cohort description of the ATTACH study participants in the United Kingdom, the United States, and Mexico. Additionally, we assess responses to daily poll questions related to COVID-19 and conduct a cross-sectional analysis of baseline assessments collected in the UK between June 26 and October 31, 2020. METHODS The ATTACH study uses smartphone app technology and online survey data collection. Participants completed poll questions related to COVID-19 2 times daily and a monthly survey assessing mental health, social isolation, physical health, and quality of life. Poll question responses were graphed using 95% Clopper–Pearson (exact) tests with 95% CIs. Pearson correlations, hierarchical linear regression analyses, and generalized linear models assessed relationships, predictors of self-reported outcomes, and group differences, respectively. RESULTS By October 31, 2020, 1405, 80, and 90 participants had consented to participate in the UK, United States, and Mexico, respectively. Descriptive data for the UK daily poll questions indicated that participants generally followed social distancing measures, but worry and negative impacts on families increased as the pandemic progressed. Although participants generally reported feeling that the reasons for current measures had been made clear, there was low trust that the government was doing everything in its power to meet public needs. In the UK, 1282 participants also completed a monthly survey (94.99% [1326/1396] White, 72.22% [1014/1404] female, and 20.12% [277/1377] key or essential workers); 18.88% (242/1282) of UK participants reported a preexisting mental health disorder, 31.36% (402/1282) reported a preexisting chronic medical illness, and 35.11% (493/1404) were aged over 65; 57.72% (740/1282) of participants reported being more sedentary since the pandemic began, and 41.89% (537/1282) reported reduced access to medical care. Those with poorer mental health outcomes lived in more deprived neighborhoods, in larger households (<i>P</i>s<.05), had more preexisting mental health disorders and medical conditions, and were younger than 65 years (all <i>P</i>s<.001). CONCLUSIONS Communities who have been exposed to additional harm during the COVID-19 pandemic were experiencing worse mental outcomes. Factors including having a medical condition, or living in a deprived neighborhood or larger household were associated with heightened risk. Future longitudinal studies should investigate the link between COVID-19 exposure, mental health, and sociodemographic and residential characteristics.

BackgroundUnderstanding the evolving treatment patterns in patients with rheumatoid arthritis (RA) is important for rheumatologists to make the best practice decisions and optimize treatment. Here, we describe treatment patterns among patients newly initiated on biologic and/or nonbiologic RA therapy over time after enrollment in the US Corrona RA registry.MethodsThis was a retrospective, cohort study of adult patients with RA enrolled in the Corrona RA registry. Patients were included in this study if they initiated therapy with conventional synthetic disease-modifying antirheumatic drug (csDMARD) monotherapy, TNF inhibitor (TNFi) monotherapy, other (non-TNFi) biologic monotherapy, or combination therapy (index therapy); initiated therapy between January 1, 2004, and December 31, 2015 (index date), after enrollment in the Corrona RA registry; had at least 6 months of follow-up time after the index date; and had at least one follow-up visit. Time periods of interest were based on the year of index therapy initiation: 2004–2007, 2008–2011, and 2012–2015.ResultsThis study included 8027 patients. csDMARD monotherapy and TNFi + csDMARD combination therapy were the most common index therapies in the registry (39.9% and 44.9%, respectively, in the 2004–2007 period; 38.6% and 38.2%, respectively, in the 2008–2011 period; and 35.2% for both in the 2012–2015 period). At therapy initiation, a higher proportion of patients who initiated other biologics, whether as monotherapies (54.0%) or in combination with csDMARD (49.9%), had high disease activity than those who initiated csDMARD monotherapy (28.4%). For 2012–2015 vs 2004–2007 and 2008–2011 periods, persistence on a given therapy appeared to decrease for the TNFi monotherapy cohort (48.2% vs 64.3% and 52.4%) and other biologic monotherapy cohort (52.3% vs 71.4% and 54.5%) over 12 months; switching from one therapy to another was common in the Corrona RA registry.ConclusionsIncreased switching from one therapy to another and decreased time on a given therapy was observed in the Corrona RA registry in the 2012–2015 period. This observation is most likely due to the increased availability of additional treatment options and/or the change in clinical focus, particularly the emphasis on achievement of treat-to-target goals of remission or low disease activity along with more aggressive treatment.

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

The ability to induce potent anti-tumor activity by stimulating 4-1BB (CD137), a key co-stimulatory receptor, makes 4-1BB an attractive immunotherapeutic target. However, a clinically tested, 4-1BB targeting monospecific antibody has been hampered by dose-limiting hepatic toxicities. To improve safety of 4-1BB targeting therapies we have developed a 4-1BB x 5T4 bispecific antibody designed to direct tumor-specific T cell responses to the tumor by stimulating 4-1BB only when co-engaged with 5T4, a tumor-associated antigen. The preclinical dataset presented here provides an overview of the mechanism of action and the efficacy and safety profile of ALG.APV-527, supporting its advancement into the clinic. ALG.APV-527 was built using the ADAPTIR™ platform with binding domains from the ALLIGATOR-GOLD® human scFv library. Its 5T4-dependent agonistic function was assessed using primary CD8+ T cells or NK cells in the presence of 5T4-expressing cells. Secretion of IFN-γ or granzyme B was measured at 72 hrs using ELISA. To measure proliferation, PBMCs were labelled with Cell Trace™ and gated CD8+ T cells were analyzed using flow cytometry. For tumor inhibition studies, the human 5T4-expressing colon carcinoma HCT116 xenograft model was used. 5T4 expression was evaluated in normal human tissues and different human tumors by immunohistochemistry. The preclinical safety profile of ALG.APV-527 was evaluated in a single and repeated dose, dose-range finding toxicology study in non-human primates (NHP). The study design included all the standard repeated dose toxicity parameters and in addition, pharmacokinetics, immunogenicity, and pharmacodynamic end-points. ALG.APV-527 induces a 5T4-dependent increase in IFN-γ and granzyme B production and enhances proliferation of T cells and NK cells. Furthermore, ALG.APV-527 inhibits tumor growth in a human 5T4-expressing colon carcinoma xenograft model. 5T4 is overexpressed in multiple solid tumors, potentially directing the activity of 4-1BB induced by ALG.APV-527 to 5T4-expressing tumors, improving the risk/benefit profile. Four doses (administered once weekly) did not cause any adverse events in the NHP toxicity study. In conclusion, ALG.APV-527 induces potent CD8+ T cell and NK co-stimulation but only in the presence of 5T4. Based on its efficacy and preclinical safety profile, ALG.APV-527 is a promising anti-cancer therapeutic for the treatment of multiple 5T4-expressing solid tumors.Citation Format: Anna Dahlman, Michelle Nelson, Jeannette Bannink, Starrla Johnson, Doreen Werchau, Anneli Nilsson, Lill Ljung, Gabriele Blahnik-Fagan, Robert Bader, Adnan Deronic, Peter Ellmark, Maria Askmyr, Gabriela Hernandez-Hoyos, Cathy McMahan, Sara Fritzell. Preclinical safety and efficacy of a tumor-directed T cell activating 4-1BB x 5T4 ADAPTIR™ bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2380.