A Monoclonal Antibody for Malaria Prevention Gaudinski, Martin R; Berkowitz, Nina M; Idris, Azza H ...
The New England journal of medicine,
08/2021, Letnik:
385, Številka:
9
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Malaria remains a cause of substantial global morbidity and mortality. In this report, an engineered monoclonal antibody showed protection against malaria infection in a controlled human infection ...model.
Several novel anti-CD20 monoclonal antibodies are currently in development with the aim of improving the treatment of B cell malignancies. Mutagenesis and epitope mapping studies have revealed ...differences between the CD20 epitopes recognized by these antibodies. Recently, X-ray crystallography studies confirmed that the Type I CD20 antibody rituximab and the Type II CD20 antibody obinutuzumab (GA101) differ fundamentally in their interaction with CD20 despite recognizing a partially overlapping epitope on CD20. The Type I CD20 antibodies rituximab and ofatumumab are known to bind to different epitopes. The differences suggest that the biological properties of these antibodies are not solely determined by their core epitope sequences, but also depend on other factors, such as the elbow hinge angle, the orientation of the bound antibody and differential effects mediated by the Fc region of the antibody. Taken together, these factors may explain differences in the preclinical properties and clinical efficacy of anti-CD20 antibodies.
Lecanemab in Early Alzheimer’s Disease van Dyck, Christopher H.; Swanson, Chad J.; Aisen, Paul ...
The New England journal of medicine,
01/2023, Letnik:
388, Številka:
1
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In a phase 3 trial, participants with early Alzheimer’s disease who received the monoclonal antibody lecanemab had less decline on measures of cognition and function at 18 months than those who ...received placebo.
Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab ...emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research.
Tumor engraftment followed by monoclonal antibody (mAb) therapy targeting tumor antigens represents a gold standard for assessing the efficiency of mAbs to eliminate tumor cells. Mouse models have ...demonstrated that receptors for the Fc portion of immunoglobulin G (FcγRs) are critical determinants of mAb therapeutic efficacy, but the FcγR-expressing cell populations responsible remain elusive. We show that neutrophils are responsible for mAb-induced therapy of both subcutaneous syngeneic melanoma and human breast cancer xenografts. mAb-induced tumor reduction, abolished in neutropenic mice, could be restored in FcγR-deficient hosts upon transfer of FcγR+ neutrophils or upon human FcγRIIA/CD32A transgenic expression. Finally, conditional knockout mice unable to perform FcγR-mediated activation and phagocytosis specifically in neutrophils were resistant to mAb-induced therapy. Our work suggests that neutrophils are necessary and sufficient for mAb-induced therapy of subcutaneous tumors, and represent a new and critical focal point for optimizing mAb-induced immunotherapies that will impact on human cancer treatment.
•Neutrophils are necessary and sufficient for mAb-induced therapy of subcutaneous syngeneic or xenograft tumors in mice.•Antitumor immunoglobulin G mAb therapy requires a Syk-dependent FcγR-induced killing of tumors by neutrophils.
Angiopoietin-like 3 is an inhibitor of lipoprotein lipase. Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3, activating lipoprotein lipase. In patients with hypercholesterolemia ...that is refractory to statin and PCSK9 inhibitor therapy, the use of evinacumab reduced plasma lipid levels by more than 50% at the maximum dose.
•Antibody–drug conjugates represent an exciting new class of cancer therapeutics.•ADCs comprise monoclonal antibodies that selectively deliver potent cytotoxic drugs.•Optimization of the antibody, ...linker and payload of an ADC is critical for success.•Recent ADCs capitalize on new cytotoxins and advances in linker and conjugation methods.
Antibody–drug conjugates (ADCs) aim to take advantage of the specificity of monoclonal antibodies (mAbs) to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells. Despite the simple concept, various parameters must be considered when designing optimal ADCs, such as selection of the appropriate antigen target and conjugation method. Each component of the ADC (the antibody, linker and drug) must also be optimized to fully realize the goal of a targeted therapy with improved efficacy and tolerability. Advancements over the past several decades have led to a new generation of ADCs comprising non-immunogenic mAbs, linkers with balanced stability and highly potent cytotoxic agents. Although challenges remain, recent clinical success has generated intense interest in this therapeutic class.
Recent advances in the discovery and development of antibody–drug conjugates have led to FDA approvals and a rich clinical pipeline of promising new cancer therapies.
Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending ...multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.
In this 12-week phase 2 trial, a humanized anti–interleukin-17 monoclonal antibody was effective for chronic plaque psoriasis. Larger studies of longer duration are necessary to assess the safety and ...efficacy of long-term treatment.
Psoriasis vulgaris (plaque psoriasis) is a chronic, frequently painful, and often debilitating skin disorder. The estimated prevalence of diagnosed psoriasis in the United States is 3%, with approximately 17% of these patients having moderate-to-severe plaque psoriasis.
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Psoriasis is characterized by inflammation and keratinocyte hyperproliferation
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thought to be the pathological consequence of a T-cell–mediated immune response to an as-yet unidentified autoantigen. Studies have shown that a subgroup of CD4+ T cells, type 17 helper T (Th17) cells, may play a specific pathological role in psoriasis.
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Type 17 helper T cells secrete a number of proinflammatory cytokines, including interleukin-17A, a member of . . .
There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association ...between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab.
We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies).
Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test).
The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.
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