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Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population.

Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom fo

CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and

Antibodies to watch in 2025.

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In pa

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… Thus, the ADC group includes bispecific ADCs, the Radioimmunotherapy group includes bispecific radioimmunotherapeutics, and the Immunoconjugate group includes immunoconjugate mixtures. … Immunoconjugates had the second lowest approval success rate (14%). …

Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer.

BACKGROUND: On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status. METHODS: We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-p

Anti-HER2 plus endocrine therapy versus anti-HER2 plus chemotherapy in hormone receptor-positive and HER2-positive metastatic breast cancer: a retrospective study.

BACKGROUND: No clinical trials demonstrated anti-HER2 plus chemotherapy (anti-HER2 + ChT) was superior to anti-HER2 plus endocrine therapy (anti-HER2 + ET) in HR + /HER2 + MBC. This study aims to compare efficacy of anti-HER2 + ET with anti-HER2 + ChT in real-world clinical practice, and analyze clinical outcome of anti-HER2 + ET as maintenance therapy after benefiting from anti-HER2 + ChT. METHODS: This study retrospectively compared two regimens: anti-HER2 + ChT vs anti-HER2 + ET, utilizing chi-square tests for response rate comparisons and Kaplan-Meier approach for survival analysis. RESU

Evaluating 225Ac and 177Lu Radioimmunoconjugates against Antibody-Drug Conjugates for Small-Cell Lung Cancer.

Interest in the use of 225Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, 225Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported preclinical solid tumor study using 225Ac RICs. In an effort to compare 225Ac RICs to other current antibody conjugates, a variety of RICs are tested against intractable small-cell lung cancer (SCLC). We directly compare, in vitro and in vivo, two pr

Mouse Strains Influence Clearance and Efficacy of Antibody and Antibody-Drug Conjugate Via Fc-FcγR Interaction.

To provide a better understanding of the pharmacokinetics-pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody-drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc-FcγR interaction by comparing antibodies that lack FcγR bin

Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1.

T-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. TIM-1 expression is also upregulated in several human cancers, most notably in renal and ovarian carcinomas, but has very restricted expression in healthy tissues, thus representing a promising target for antibody-mediated therapy. To this end, we have developed a fully human monoclonal IgG1 antibody specific for the extracellular domain of TIM-1. This antibody was shown to bin

TP53 loss creates therapeutic vulnerability in colorectal cancer.

TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene

Contraceptive vaccines based on the zona pellucida glycoproteins for dogs and other wildlife population management.

Zona pellucida (ZP) glycoproteins, by virtue of their critical role in fertilization, have been proposed as candidate antigens for the development of contraceptive vaccines. In this review, the potential of a ZP-based contraceptive vaccine for the management of wildlife population, with special reference to street dogs, is discussed. Immunization of various animal species, including female dogs, with native porcine ZP led to inhibition of fertility, which was associated with the ovarian dysfunction. Immunization of female dogs with Escherichia coli-expressed recombinant dog ZP glycoprotein-3 (

In vivo monitoring of intranuclear p27(kip1) protein expression in breast cancer cells during trastuzumab (Herceptin) therapy.

INTRODUCTION: Trastuzumab, a humanized antibody directed against the Her2 receptor, induces the expression of p27(kip1), an intranuclear cyclin-dependent kinase inhibitor in some breast cancer cells. The aim of this study was to develop a radioimmunoconjugate (RIC) to monitor trastuzumab-induced p27(kip1) protein up-regulation in vivo. MATERIALS AND METHODS: Anti-p27(kip1) IgG was purified, and conjugated to diethylenetriaminopentaacetate, to allow radiolabeling with (111)In for in vivo detection. Then tat peptide (GRKKRRQRRRPPQGYG), containing a nuclear localization sequence (underlined), wa

CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with foc

The kinetics of CD154 (CD40L) expression in peripheral blood mononuclear cells of healthy subjects in liver allograft recipients and X-linked hyper-IgM syndrome.

UNLABELLED: The costimulatory pathways play a key role in T cell activation during allograft rejection (AR). Inhibition of the T cell costimulatory molecule CD154 (CD40 ligand) has been effective in producing long-term allograft survival in rodents and non-human primates. The role of the CD40-CD154 pathway in human orthotopic liver transplantation (OLT) has not been examined. AIM: To describe the patterns of CD154, CD69 and CD152 (CTLA4) expression in OLT recipients and to determine their temporal relationship to AR. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 15 O

Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions.

The B7 family of costimulatory molecules likely includes members distinct from B7.1 (CD80) and B7.2 (CD86). After stimulation with IFN-gamma or TNF-alpha, human myoblasts selectively express BB-1, but not B7.1 or B7.2. BB-1 is detected by anti-BB-1, a mAb cross-reacting with B7.1 (but not B7.2) and an as yet undefined costimulatory molecule. The absence of B7.1 and B7.2 in BB-1-positive myoblasts was confirmed by RT-PCR. The molecule detected by anti-BB-1 is functional, because anti-BB-1 mAb and CTLA4Ig (but not anti-B7.1- or anti-B7.2-specific mAbs) completely inhibit Ag presentation by cytok

Report on the 56th ASH Annual Meeting, San Francisco, 4-9 December 2014.

The 56th annual ASH (American Society of Haematology) meeting was held in San Francisco (CA). More than 3,000 abstracts were selected for presentation due to the huge amount of information from basic science to clinical experience. The future direction in haematoncology is targeted therapies for most diseases; for instance, anti-PD-1 and CAR-T cells in lymphoproliferative disorders and novel immunomodulatory agents active in the contest of bone marrow milieu in multiple myeloma. On the other hand, in aggressive haematological diseases (AML, ALL), clinical studies demonstrated the feasibility o

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… The addition of immunoconjugate gentuzumab ozogamicin to standard induction therapy (7 + 3) has been shown to improve outcome [ 8 , 9 ]. A common standard for post-remission therapy is repeated cycles of intermediate high-dose cytarabine. … Brentuximab vedotin (anti-Cd30 Ab) is used as immunoconjugates, which includes phase-2 study. Ibrutinib (BRUTON’s TKI) is used as BCR pathway inhibitors, which include phase 2 and 3 including combinations [ 21 ]. …

Mechanistic considerations for the use of monoclonal antibodies for cancer therapy.

Since the approval of rituximab in 1997, monoclonal antibodies (mAbs) have become an increasingly important component of therapeutic regimens in oncology. The success of mAbs as a therapeutic class is a result of great strides that have been made in molecular biology and in biotechnology over the past several decades. Currently, there are 14 approved mAb products for oncology indications, and there are ten additional mAbs in late stages of clinical trials. Compared to traditional chemotherapeutic agents, mAbs have several advantages, including a long circulating half-life and high target speci

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… Delivery of toxic payloads (immunoconjugates) The use of mAbs to deliver a highly potent payload to tumor sites is perhaps the epitome of Ehrlich’s ‘magic bullet’ hypothesis. … Radioimmunoconjugates, the final class of immunoconjugates, employ mAbs as targeting agents for selective delivery radionuclides to tumor cells. …

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial.

BACKGROUND: Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkin's lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerat…

Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation.

Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginnin

Flow cytometric assessment of human peripheral blood mononuclear cells in response to a coccidioidal antigen.

The in vitro responses of peripheral blood mononuclear cells (PBMC) from healthy immune and non-immune donors were assessed by flow cytometry after incubation with the coccidioidal antigen toluene spherule lysate (TSL). After 120 h of incubation with 100 microg ml(-1) of TSL, expression of the activation markers CD69, CD25 and human leukocyte antigen-DR were all significantly increased in CD3+ lymphocytes from immune donors compared to non-immune donors (P < 0.03 for all). No differences in the surface expression of the costimulatory molecules CD28, CD152 or CD154 was seen between immune and n