Showing papers by "Patrick A. Baeuerle published in 2018"

Antiviral Activity of HIV gp120-Targeting Bispecific T Cell Engager Antibody Constructs.

Abstract: Today's gold standard in HIV therapy is combined antiretroviral therapy (cART). It requires strict adherence by patients and lifelong medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency but cannot cure patients. The bispecific T cell-engaging (BiTE) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. Here, we generated BiTE antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1 + 2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3e scFv. These engineered human BiTE antibody constructs showed engagement of T cells for redirected lysis of HIV gp120-transfected CHO cells. Furthermore, they substantially inhibited HIV-1 replication in peripheral blood mononuclear cells (PBMCs) as well as in macrophages cocultured with autologous CD8+ T cells, the most potent being the human CD4(1 + 2) BiTE [termed CD(1 + 2) h BiTE] antibody construct and the CD4(1 + 2)L17b BiTE antibody construct. The CD4(1 + 2) h BiTE antibody construct promoted HIV infection of human CD4-/CD8+ T cells. In contrast, the neutralizing B12 and the VRC01 BiTE antibody constructs, as well as the CD4(1 + 2)L17b BiTE antibody construct, did not. Thus, BiTE antibody constructs targeting HIV gp120 are very promising for constraining HIV and warrant further development as novel antiviral therapy with curative potential.IMPORTANCE HIV is a chronic infection well controlled with the current cART. However, we lack a cure for HIV, and the HIV pandemic goes on. Here, we showed in vitro and ex vivo that a BiTE antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE antibody constructs display efficient killing of gp120-expressing cells and inhibited replication in ex vivo HIV-infected PBMCs or macrophages. We believe that BiTE antibody constructs recognizing HIV gp120 could be a very valuable strategy for a cure of HIV in combination with cART and compounds which reverse latency.

Pharmacokinetic and Pharmacodynamic Relationship of Blinatumomab in Patients with Non-Hodgkin Lymphoma.

Abstract: Background Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct targeting CD3e on T cells and CD19 on B cells. We describe the relationship between pharmacokinetics (PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes, serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL). Methods In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 µg/m2/day). PD changes were analyzed with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under the concentration-versus-time curve (AUCcum). Results B-cell depletion occurred within 48 hours at doses ≥5 µg/m2/day, followed first-order kinetics, and was blinatumomab exposure-dependent. Change in tumor size depended on systemic blinatumomab exposure and treatment duration and could be fitted to an Emax model, which predicted a 50% reduction in tumor size at AUCcum of ≥1,340 h×µg/L and Css of ≥1,830 pg/mL, corresponding to a blinatumomab dose of 47 µg/m2/day for 28 days. The magnitude of transient cytokine elevation, observed within 1-2 days of infusion start, was dose-dependent, with less pronounced elevation at low starting doses. Conclusion B-lymphocyte depletion following blinatumomab infusion was exposure-dependent. Transient cytokine elevation increased with dose; it was less pronounced at low starting doses. Tumor response was a function of exposure, suggesting utility for the PK/PD relationship in dose selection for future studies, including NHL and other malignant settings.

Abstract 1773: HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer

Abstract: Metastatic, castrate-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients each year in the US alone, and roughly 27,000 patients will succumb to it every year. Once metastasized beyond regional lymph nodes, the 5-year survival rate is 30%. While novel therapeutics like abiraterone and enzalutamide have improved the treatment options for mCRPC, no curative treatment is available, and new therapies are urgently needed. HPN424 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) under development for the treatment of mCRPC. It is designed to simultaneously bind to CD3ϵ on T cells and to prostate specific membrane antigen (PSMA, FOLH1) on prostate cancer cells. A third domain of HPN424 binds non-covalently to serum albumin for extension of serum half-life. PSMA is expressed in >90% of malignant lesions of patients, and outside the central nervous system, its expression on normal tissue is largely restricted to the prostate. HPN424 binds human PSMA with sub-nanomolar affinity. When incubated in co-cultures with resting, human T cells and prostate cancer cells, it activates T cells and induces cytokine production, proliferation and redirected target cell killing with EC50 values in the single digit picomolar range. When administered to mice bearing human prostate cancer xenografts and human T cells, HPN424 eradicates subcutaneous tumors. The affinities of HPN424 for human and cynomolgus monkey CD3 and albumin are comparable, while HPN424 binds only marginally to cynomolgus PSMA. HPN424 is very well tolerated in non-human primates, even at high doses, indicating that CD3-binding has little if any pharmacological effect in the absence of target binding. Pharmacokinetic analysis supports weekly administration in humans. Our preclinical data suggest that HPN424 will be highly efficacious, safe and convenient for the treatment of patients with mCRPC. Citation Format: Bryan Lemon, Wade Aaron, Richard Austin, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Kathryn Kwant, Che-Leung Law, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1773.

Targeted checkpoint inhibitors and methods of use

Abstract: Provided herein are inducible target-binding protein, comprising a single polypeptide chain comprising - two or more inactive immune checkpoint protein binding domains, two or more target antigen binding domains, one or more half-life extension domains, and one or more protease cleavage sites, compositions thereof and methods of use.

Abstract 1781: HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors

Abstract: Mesothelin (MSLN) is a GPI-linked tumor antigen overexpressed in a variety of solid tumors, including ovarian, pancreatic, lung and triple-negative breast cancer. Normal tissue expression is restricted to single-cell, mesothelial layers lining the pleural, pericardial, and peritoneal cavities. Overexpression of MSLN is associated with poor prognosis in lung adenocarcinoma and triple-negative breast cancer. MSLN has been used as cancer target antigen for numerous modalities, including immunotoxins, vaccines, antibody drug conjugates and CAR-T cells. Early signs of clinical efficacy have validated MSLN as target, but therapies with improved efficacy are still needed to address the significant, unmet medical need posed by MSLN-expressing cancers. HPN536 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) designed to simultaneously bind to MSLN on tumor cells and to CD3ϵ on T cells with an affinity of 1 nM and 14 nM, respectively. Transient bispecific binding leads to the formation of an immunological cytolytic synapse, T cell activation and redirected tumor cell killing. A third domain of HPN536 binds non-covalently to serum albumin with an affinity of 8 nM to extend serum half-life life. Because TriTACs are built using single domain antibodies, TriTACs are much smaller than full size antibodies and are anticipated to demonstrate improved penetration of human tumors compared to full sized antibodies. HPN536 is produced by eukaryotic cell culture and secreted as a highly stable, single polypeptide. It binds with similar affinity to human and cynomolgus MSLN, albumin and CD3. When incubated in co-cultures with resting, human or cynomolgus T cells and human tumor cells, T cells are induced to release cytokines, to proliferate, and to specifically lyse MSLN-positive target cells with EC50 values at single-digit picomolar concentrations. In an exploratory toxicological study in non-human primates, HPN536 was well tolerated and showed pharmacokinetics in support of weekly dosing in humans. Preclinical characterization suggests that HPN536 is an efficacious and safe novel therapeutic candidate for the convenient treatment of patients with MSLN-expressing malignancies. Citation Format: Richard Austin, Wade Aaron, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Che-Leung Law, Kathryn Kwant, Bryan Lemon, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1781.

Innate immune cell inducible binding proteins and methods of use

Abstract: Provided herein are conditionally activated antigen-binding proteins comprising a protease-activated domain binding to an innate immune cell, at least one half-life extension domain, and two or more domains binding to one or more target antigens. Also provided are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such antigen-binding proteins. Also disclosed are methods of using the disclosed antigen-binding proteins in the prevention, and/or treatment diseases, conditions and disorders.

Abstract 3814: TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life

Abstract: T cell engagers are antibody-based therapeutics that transiently tether T cells via the T cell receptor complex (TCR) to surface antigens on tumor cells. This leads to activation of T cells and redirected lysis of the attached target cell. The therapeutic potential of this modality was demonstrated by blinatumomab, a CD19/CD3-bispecific T cell engager approved for the treatment of adult patients with relapsed/refractory acute lymphoblastic leukemia. Despite success of this T cell-engaging therapy in a hematologic malignancy, clinical studies in solid tumors with other T cell engagers have been less encouraging so far. The TriTAC (Tri-specific T cell Activating Construct) platform was developed to address shortcomings of existing T cell engagers, including short serum half-life, limited tissue penetration, and suboptimal activity. TriTAC constructs are made of a single polypeptide designed to bind to a cancer surface antigen, the CD3 epsilon subunit of the TCR, and to human serum albumin. CD3 is bound by a single-chain variable fragment (scFv) while both tumor targeting and albumin binding are achieved by single domain antibodies. The latter allow TriTACs to be very small, stable, and easily produced and purified. Noncovalent binding to serum albumin has been validated as an effective way to extend the serum half-life of other proteins up to several weeks. Even though TriTACs have three binding domains, their overall size is only ~50 kDa, one third of the size of a monoclonal antibody. This is expected to allow for faster diffusion into human tumor tissues than is possible with antibodies given the high interstitial pressure and dense extracellular matrix in solid tumors. TriTACs can induce T cell to kill tumor cells in vitro at single-digit picomolar to femtomolar concentrations with concomitant induction of inflammatory cytokine release and T cell proliferation. TriTACs can diffuse much faster across an extracellular matrix than antibodies, and eradicate tumors in mouse xenograft models supplemented with human T cells. In nonhuman primates, TriTAC molecules have serum half-lives of approximately 4 days, and appear well tolerated. Citation Format: Holger Wesche, Wade Aaron, Richard J. Austin, Patrick A. Baeuerle, Adrie Jones, Bryan Lemon, Kenneth Sexton, Timothy Yu. TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3814.

Abstract 3589: Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy

Abstract: Despite success in treating hematological malignancies, T cells expressing chimeric antigen receptors (CARs) have shown poor efficacy in solid tumor indications. The poor utility of CARs is thought to be due to a number of factors including T cell exhaustion and a lack of persistence. Utilizing only the CD3ζ chain of six distinct T cell receptor subunits in combination with a costimulatory domain, the CARs bypass the natural TCR signaling complex. The failure to initiate and harness a complete TCR response is arguably a primary underlying factor preventing CAR-T cell success in solid tumor indications. Here, we present a novel T cell engineering platform: T Cell Receptor Fusion Constructs (TRuC™s), which target tumors in a MHC non-restricted fashion. Unlike CARs, the constructs integrate into the TCR complex, harnessing the full potential of natural T cell activation, effector function and regulation. Here we demonstrate preclinical evidence underscoring the efficacy of TRuC™-T cells re-programmed to target the solid tumor antigen mesothelin (TC-210). TC-210 showed robust anti-tumor activity in vitro and in vivo in mesothelioma, lung and ovarian tumor models. Surprisingly, this activity was associated with less proinflammatory cytokine production compared to CAR-T cells with the same binder and was supported by strong TRuC™-T cell persistence. Taken together, mesothelin targeting TRuC™-T cells have potent anti-tumor activity and present a promising approach for treating mesothelin-expressing solid tumors. Citation Format: Jian Ding, Ekta Patel, Patrick Tavares, Justin Quinn, Rashmi Choudhary, Bonnie Le, Olga Kiner, Solly Weiler, Daniel R. Getts, Patrick Baeuerle, Robert Hofmeister. Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3589.

Abstract 3584: Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors

Abstract: T cells expressing chimeric antigen receptors (CARs) have demonstrated remarkable clinical benefit in certain hematological malignancies albeit with side effect such as cytokine release syndrome, on Target off tumor response and limited efficacy in solid tumors. Here, we present the preclinical evaluation of a novel T cell engineering platform designed to overcome potential hurdles of CARs and other T cell receptor modalities. Specifically, we have generated novel T Cell Receptor Fusion Constructs (TRuC™s) that fuse binder domains to subunits of the T cell receptor. These constructs when introduced using lentiviral technology, integrate into endogenous TCR, reprograming T cells to target tumor antigen in a non-major histocompatibility complex (MHC) restricted fashion and harnessing the full spectrum of TCR signaling. TRuC™ variants were constructed by recombinant fusion of an scFv or sdAb to various TCR subunits via a flexible linker sequence. Likewise, CD28ζ and 41BBζ CARs were generated using the same binders for side-by-side comparison. We demonstrated that TRuC™ variants can effectively reprogram T cells to recognize tumor surface antigens in a non-MHC-restricted fashion. TRuC™s are distinct from CARs in their ability to activate T cells through the entire TCR without additional costimulatory domains. In vitro, TRuC™ T cells were equally potent as CAR T cells in eliminating tumor cells. Compared to CAR-T cells, TRuC-T cells produced lower cytokine levels and proliferated less. Despite these difference, TRuC™ T cells were more efficient in clearing tumors in subcutaneous Raji and MSTO-211H mesothelioma models. Our findings support the development of TRuC-T cells for the treatment of solid tumors. Citation Format: Ekta Patel, Jian Ding, Nikolaus Thorausch, Janani Krishnamurthy, Rashmi Choudhary, Solly Weiler, Bonnie Le, Patrick Tavares, Adam Zieba, Justin Quinn, Yan Wang, Wolfgang Schamel, Irene Scarfo, Marcela Maus, Patrick Baeuerle, Dainel Getts, Robert Hofmeister. Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3584.

삼중특이성 결합 단백질 및 사용 방법

Abstract: 본원은 CD3에 결합하는 도메인, 반감기 연장 도메인, 및 표적 항원에 결합하는 도메인을 포함하는 삼중특이성 항원 결합 단백질을 제공한다. 또한, 본원은 상기 삼중특이성 항원 결합 단백질의 약학 조성물, 상기 삼중특이성 항원 결합 단백질을 제조하기 위한 핵산, 재조합 발현 벡터 및 숙주 세포를 제공한다. 또한, 질환, 병태 및 질병의 예방 및/또는 치료에, 개시된 삼중특이성 항원 결합 단백질을 사용하는 방법을 개시한다.