Browsing by Subject "Immunoconjugates"

Now showing 1 - 5 of 5
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    First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody-Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast or Gastric Cancer
    (American Association for Cancer Research, 2021) Pegram, Mark D.; Hamilton, Erika P.; Tan, Antoinette R.; Storniolo, Anna Maria; Balic, Kemal; Rosenbaum, Anton I.; Liang, Meina; He, Peng; Marshall, Shannon; Scheuber, Anita; Das, Mayukh; Patel, Manish R.; Medicine, School of Medicine
    MEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2-positive tumor cells in vitro This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)-all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.
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    Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial
    (American Association for Cancer Research, 2022) Boni, Valentina; Fidler, Mary J.; Arkenau, Hendrik-Tobias; Spira, Alexander; Meric-Bernstam, Funda; Uboha, Nataliya; Sanborn, Rachel E.; Sweis, Randy F.; LoRusso, Patricia; Nagasaka, Misako; Garcia-Corbacho, Javier; Jalal, Shadi; Harding, James J.; Kim, Stella K.; Miedema, Iris H. C.; Vugts, Danielle J.; Huisman, Marc C.; Zwezerijnen, Gerben J. C.; van Dongen, Guus A. M. S.; van der Houven van Oordt, C. Willemien Menke; Wang, Song; Dang, Tam; Zein, Ivan A.; Vasiljeva, Olga; Lyman, Susan K.; Paton, Virginia; Hannah, Alison; Liu, Joyce F.; Medicine, School of Medicine
    Purpose: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. Patients and methods: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). Results: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. Conclusions: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.
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    Reducing target binding affinity improves the therapeutic index of anti-MET antibody-drug conjugate in tumor bearing animals
    (Public Library of Science, 2024-04-17) Datta-Mannan, Amita; Choi, Hiuwan; Jin, Zhaoyan; Liu, Ling; Lu, Jirong; Stokell, David J.; Murphy, Anthony T.; Dunn, Kenneth W.; Martinez, Michelle M.; Feng, Yiqing; Medicine, School of Medicine
    Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the 111In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.
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    Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer
    (American Association for Cancer Research, 2022) Ray, Upasana; Jung, Deok-Beom; Jin, Ling; Xiao, Yinan; Dasari, Subramanyam; Bhattacharya, Sayantani Sarkar; Thirusangu, Prabhu; Staub, Julie K.; Roy, Debarshi; Roy, Bhaskar; Weroha, S. John; Hou, Xiaonan; Purcell, James W.; Bakkum-Gamez, Jamie N.; Kaufmann, Scott H.; Kannan, Nagarajan; Mitra, Anirban K.; Shridhar, Viji; Medical and Molecular Genetics, School of Medicine
    Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases. Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.
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    Treatment of CD30-Expressing Germ Cell Tumors and Sex Cord Stromal Tumors with Brentuximab Vedotin: Identification and Report of Seven Cases
    (AlphaMed Press, 2018-03) Albany, Costantine; Einhorn, Lawrence; Garbo, Lawrence; Boyd, Thomas; Josephson, Neil; Feldman, Darren R.; Department of Medicine, IU School of Medicine
    BACKGROUND: Cytotoxic therapy for relapsed and refractory germ cell tumors or metastatic sex cord stromal tumors is rarely effective and is often accompanied by high adverse event rates. Expression of CD30 has been observed in testicular cancers, and patients with CD30-expressing embryonal carcinomas have worse progression-free survival and overall survival than those with CD30-negative tumors. The objective of this study (NCT01461538) was to characterize the antitumor activity of brentuximab vedotin in patients with CD30-expressing nonlymphomatous malignancies. Enrolled patients included seven patients with relapsed or refractory germ cell tumors or metastatic sex cord stromal tumors described in this case series. MATERIALS AND METHODS: Forty patients with relapsed or refractory germ cell tumors, metastatic sex cord stromal tumors, or testicular tumors were screened for CD30 expression; 14 patients had tumors that expressed CD30. Seven patients with CD30-expressing testicular cancer were enrolled in the treatment study: five patients with germ cell tumors, one patient with a Leydig cell tumor, and one patient with a Sertoli cell tumor. Patients were treated with brentuximab vedotin at initial doses of 1.8 or 2.4 mg/kg every 3 weeks. Response assessments were performed at cycles 2 and 4 and every 4 cycles thereafter while the patient was receiving treatment. RESULTS: Two of seven patients achieved an objective response, including one durable complete response and one partial response at a single time point. Both responding patients had germ cell tumors. Treatment with brentuximab vedotin was generally well tolerated. CONCLUSION: Treatment of relapsed or refractory germ cell tumors with brentuximab vedotin can induce durable responses with a manageable toxicity profile. IMPLICATIONS FOR PRACTICE: This case series of seven patients with relapsed or refractory CD30-expressing germ cell tumors (GCTs) or sex cord stromal tumors demonstrates that brentuximab vedotin has activity against GCTs and is well tolerated in heavily pretreated patients with these aggressive tumor types. One patient achieved a complete response that has been durable for almost 4 years since the discontinuation of treatment with brentuximab vedotin. Therefore, brentuximab vedotin may be a valuable option for physicians who care for this difficult-to-treat patient population.