Xencor (United States)

The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.

An insufficient quantity of functional T cells is a likely factor limiting the clinical activity of T-cell bispecific antibodies, especially in solid tumor indications. We hypothesized that XmAb24306 (efbalropendekin alfa), a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein, may potentiate the activity of T-cell dependent (TDB) antibodies. The activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in the upregulation of the IL-2/15Rβ (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to IL-15. XmAb24306 enhanced T-cell bispecific antibody-induced CD8+ and CD4+ T-cell proliferation and expansion. In vitro combination of XmAb24306 with cevostamab or anti-HER2/CD3 TDB resulted in significant enhancement of tumor cell killing, which was reversed when T-cell numbers were normalized, suggesting that T-cell expansion is the main mechanism of the observed benefit. Pretreatment of immunocompetent mice with a mouse-reactive surrogate of XmAb24306 (mIL-15-Fc) resulted in a significant increase of T cells in the blood, spleen, and tumors and converted transient anti-HER2/CD3 TDB responses to complete durable responses. In summary, our results support the hypothesis that the number of tumor-infiltrating T cells is rate limiting for the activity of solid tumor-targeting TDBs. Upregulation of CD122 by TDB treatment and the observed synergy with XmAb24306 and T-cell bispecific antibodies support clinical evaluation of this novel immunotherapy combination.

Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.

BackgroundT cells in the tumor micro-environment require TCR/MHC engagement and co-stimulatory receptor engagement to achieve optimal activation. Tumor cells lack expression of CD28 ligands, so we hypothesized that activation of CD28 signaling at the T cell/tumor cell interface could enhance anti-tumor activity. We designed PDL1 x PDL2 x CD28 trispecific antibodies that conditionally costimulate CD28 only in the presence of PDL1 or PDL2 expression, and TCR engagement. As PD1 signaling has been shown to directly inhibit CD28 costimulation, this novel bispecific modality has potential to promote CD28 costimulation while simultaneously preventing the suppression of the same signal. Furthermore, since CD3 bispecific T cells engagers are known to indirectly promote PDL1 expression, PDL1 x PDL2 x CD28 trispecific antibodies can potentially be applied in combination to CD3-bispecific T cell engagers to enhance their activity.MethodsWe developed a CD28 antibody that is agonistic only under the context of TCR engagement. We paired this CD28 binding domain with PDL1 and PDL2 Fab binding domains that share a common light chain to generate PDL1 x PDL2 x CD28 trispecifics monovalent for each of the three antigens. We optimized the affinity for each of the antigens for potent blockade of PDL1 and PDL2 and enable CD28 costimulation across a range of PDL1 and PDL2 cell surface densities. Cell based assays with different TCR engagement modalities were utilized to describe the function of trispecifics including, CD3-stimulated T cells cocultured with cancer cell lines, CMV+ T cells recognizing cancer cells expressing pp65-derived NLV peptide, and Mixed Lymphocyte Reactions. Cell based assays measured IL2 and IFNγ release, T cell proliferation and cancer-cell death as readouts for activity.ResultsPDL1 x PDL2 x CD28 trispecifics block PDL1 and PDL2 binding to PD1 in both solid phase and cell-based assays. PDL1 and PDL2 blockade led to enhanced cytokine secretion from human mixed lymphocyte reactions. Target cell expression of either PDL1 or PDL2 was shown to be sufficient to promote CD28 co-stimulation leading to acute IL2 release of cocultures of CD3-stimulated PBMC with cancer cell lines. In a more physiologically relevant model of TCR engagement, PDL1 x PDL2 x CD28 trispecifics enhanced T cell activation in a CMV-recall assay. When in combination with CD3-targeted T cell engagers, PDL1 x PDL2 x CD28 trispecifics enhanced T cell proliferation and TDCC activity.ConclusionsData warrant further development of PDL1 x PDL2 x CD28 trispecifics for treatment of solid tumors.

BackgroundInterleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Mature IL18 promotes the expansion, survival, and cytotoxicity of T and NK cells expressing the heterodimeric IL18 receptor. Preclinical studies with recombinant IL18 have demonstrated anti-tumor activity in animal models, including impressive synergy with both immune checkpoint inhibitors and CAR-T therapy. However, clinical development as a single agent exhibited poor pharmacokinetics and an overall lack of efficacy despite heavy dosing. IL18 participates in a negative feedback loop with IL18 binding protein (IL18BP), a very high affinity natural inhibitor induced by IFNγ. As IL18BP upregulation was observed in early phase clinical trials, it likely limited the efficacy of recombinant IL18.MethodsPrior work at Xencor demonstrated that reduced-potency IL15/IL15Rα-Fc fusion proteins exhibited superior pharmacokinetics, pharmacodynamics, and safety in non-human primates through reduction of receptor-mediated clearance. Following that principle, we generated monovalent IL18-Fc fusions upon our XmAb® heterodimeric Fc platform and introduced substitutions that could modulate IL18 stability, affinity toward the IL18 heterodimeric receptor, and affinity toward IL18BP.ResultsTo address IL18’s poor native stability, we engineered a disulfide bridge into the cytokine’s structure which increased the thermal denaturation temperature from 45 °C to 65 °C. This had beneficial effects on the cytokine’s yield and solution behavior, and translated into a significant improvement of PK in mice. Variants at IL18 positions along the IL18 receptor and IL18BP interfaces were explored in vitro by measuring PD-L1 induction on KG-1 cells, with and without a high concentration of IL18BP. Recombining hits generated a potency series with variants exhibiting over a 2,000-fold reduction in PD-L1 induction potency as compared to WT IL18-Fc. Importantly, we identified variants that no longer detectably bound IL18BP, relieving natural inhibition of our engineered IL18-Fc. In vivo immune-mediated inflammation by our lead IL18-Fc, XmAb143, was explored in human PBMC engrafted mouse models of graft versus host disease (GvHD). We observed dose-dependent exacerbation of GvHD, with corresponding dramatic increases in the numbers, activation, and IFNy release of T and NK cells as compared to a human PBMC only control. Conversely, XmAb143 pharmacodynamics in cynomolgus monkey pilot tox studies was observed only at higher doses, and serum half-life improved from hours to days over WT IL18-Fc.ConclusionsXmAb143, our engineered monovalent IL18-Fc fusion demonstrates insensitivity to IL18BP inhibition, robust inflammation activity in vivo, and improved pharmacokinetics in mice and cynomolgus monkeys.

Background: Plamotamab (XmAb13676) is a humanized bispecific antibody that binds both CD20 and CD3 and thereby recruits cytotoxic T cells to kill CD20-expressing malignant cells. In a Phase 1 trial in B-cell malignancies, plamotamab was generally well tolerated, with no Grade ≥ 3 cytokine release syndrome events at the recommended Phase 2 dose (RP2D) regimen, and other safety events being generally mild or moderate in severity. The RP2D demonstrated clinical activity in subjects with relapsed/refractory (R/R) non-Hodgkin lymphoma. The objective response rate (ORR) in follicular lymphoma (FL) was 100% (4/4), with a complete response rate of 50% (2/4). The ORR in diffuse large B-cell lymphoma (DLBCL) was 40% (2/5). Subjects were heavily pretreated with a median of 4 prior lines of therapy (range 2-8) for FL and a median of 5 lines of therapy for DLBCL (range 4-10); all DLBCL subjects received prior CAR-T (ASH 2021 Abstract 2494). TAFA is a humanized CD19-directed cytolytic monoclonal antibody that contains an IgG1/2 hybrid Fc domain with 2 amino acid substitutions to modify the Fc-mediated functions of the antibody and mediates B-cell lysis through apoptosis and immune effector mechanisms. TAFA is indicated for use in the US and EU in combination with LEN for treating adults with R/R DLBCL who are not eligible for autologous stem cell therapy (ASCT). Addition of the CD3xCD20 plamotamab to the TAFA+LEN doublet offers the potential for improved efficacy through recruitment of distinct T cell and Fc-mediated cytotoxic mechanisms while also overcoming tumor resistance that might otherwise arise from single antigenic loss of either CD19 or CD20. These characteristics support a study of the combination of plamotamab, TAFA, and LEN. Aims: This trials-in-progress abstract details eligibility criteria and trial design of the Phase 2 XmAb13676-03 trial. Methods: This randomized, multicenter, open-label, 2-part study is intended to compare the safety and efficacy of plamotamab+TAFA+LEN vs TAFA+LEN in adult subjects with DLBCL who have relapsed or are refractory to ≥ 1 prior line of therapy and are ineligible for or refuse ASCT. Prior therapy must include multiagent chemoimmunotherapy that includes an anti-CD20 mAb. The trial consists of 2 parts, performed sequentially; Part 1 is a 2-cohort safety run-in that serves to identify the optimal dose of plamotamab (20 or 50 mg) to be administered with TAFA+LEN (shown in figure). Part 2 randomizes 200 subjects in a 1:1 ratio to the 2 treatment arms (with dosing regimen selected from Part 1), stratified by international prognostic index risk score, number of lines of prior therapy, and primary refractory (y/n). Eligible subjects must have documented diagnosis of DLBCL, not otherwise specified, CD20+ and CD19+ lymphoma, and relapsed or primary refractory disease. Exclusion criteria include central nervous system (CNS) lymphoma or secondary CNS involvement. Subjects with prior CAR-T are eligible if current biopsy is CD19+. Results: The primary objectives are safety and efficacy. The primary endpoint in Part 1 is safety and the primary endpoint in Part 2 is progression-free survival with disease assessed at regular intervals. Response, overall survival, and duration of response are secondary endpoints. Subjects continue study treatment until progression and are followed for long-term survival. Image:Summary/Conclusion: The XmAb13676-03 trial is registered at EudraCT (2021-003658-22) and anticipates enrolling in centers in the US, EU, and Asia.

TPS5097 Background: Although immune checkpoint inhibitor (ICI) monotherapy has shown limited clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC), better outcomes have been observed with combination anti-PD-1/CTLA-4 therapy. In addition, whereas response rates are low in unselected mCRPC populations, tumors with selected molecular characteristics, including those associated with aggressive variant disease, CDK12 inactivation, and microsatellite instability high (MSI-H) status, have shown increased sensitivity to ICIs. Finally, altering the tumor microenvironment to promote antitumor immunity by combining ICIs with chemotherapy or targeted agents also has potential to increase clinical benefit. Vudalimab (XmAb20717) is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4 and binds preferentially to PD-1/CTLA-4 dual-positive cells. In a Phase 1 study, vudalimab monotherapy was generally well-tolerated and associated with complete and partial responses in patients with multiple tumor types, including mCRPC. This Phase 2 study is designed to evaluate the safety and antitumor activity of vudalimab in combination with other anticancer agents or alone in subgroups of mCRPC patients with and without specific tumor molecular subtypes. Methods: This multicenter, open-label study is being conducted at approximately 20 sites in the United States. Patients with mCRPC that progressed following treatment with ≥ 2 prior lines of anticancer therapy are enrolled into the following parallel cohorts based on the presence or absence of molecular abnormalities from prior sequencing of metastatic tumor: aggressive variant (Cohort 1), homologous recombination deficient or CDK12 mutation positive PARP inhibitor progressor (Cohort 2) or PARP inhibitor naïve (Cohort 3), MSI-H or mismatch repair deficient (Cohort 4), and no targetable mutation (Cohort 5). All patients will receive vudalimab 10 mg/kg intravenously every 2 weeks. Cohorts 1, 2, and 5 (n = 20 each) also will receive carboplatin AUC 4 + cabazitaxel 20 mg/m2 (or docetaxel 60 mg/m2, if not received prior) every 3 weeks; Cohort 3 (n = 20) also will receive olaparib 300 mg 2x/day; and Cohort 4 (n = 5) will receive vudalimab monotherapy. The primary objective is to evaluate the safety/tolerability of treatment based on adverse events. Secondary objectives include evaluating objective response (RECIST 1.1, as modified by PCWG3), radiographic progression-free survival, and PSA response. Exploratory objectives include assessing pharmacodynamic activity in peripheral blood and tumor, and correlations of response with cohort-specific molecular tumor characteristics. Enrollment has been initiated. Clinical trial information: NCT05005728.