Development of a qualified pharmacokinetic bioassay to support preclinical and clinical studies of MM-008, a non-hormonal contraceptive antibody

开发合格的药代动力学生物测定法以支持非激素避孕抗体 MM-008 的临床前和临床研究

• 批准号: 10459074
• 负责人: Keiichiro Kushiro
• 金额: $ 27.77万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459074
• 关键词: Adherence; Affinity; Agglutination; Animal Model; Animals; Antibodies; Antigen Targeting; Antigens; Binding; Biodistribution; Biological; Biological Assay; Biomanufacturing; Cervical; Clinic; Clinical; Clinical Research; Contraceptive Agents; Contraceptive Usage; Contraceptive Vaccines; Contraceptive methods; Contracts; Copper; Critical Pathways; Detection; Development; Dose; Drug Kinetics; Engineering; Ensure; Enzyme-Linked Immunosorbent Assay; Exogenous Hormone Therapy; Female; Fertility; Film; Formulation; Healthcare Systems; Hormones; Human; IgG1; Immune; Immunoglobulin G; Immunoglobulin Idiotypes; Infertility; Lead; Liquid substance; Literature; Measures; Medical; Methods; Modeling; Monoclonal Antibodies; Mucous body substance; Phase; Pregnancy; Process; Rattus; Reproducibility; Robot; Sampling; Sensitivity and Specificity; Serum; Sheep; Sperm Agglutination; Sperm Motility; Spermatozoa antibody; Streptavidin; System; Testing; Toxicokinetics; Vagina; Vaginal Ring; Vaginal delivery procedure; Variant; Woman; Work; assay development; base; capsule; cell motility; cervicovaginal; clinical development; cost; design; detection assay; detection method; detection sensitivity; early phase clinical trial; egg; hormonal contraception; insight; male; monoclonal antibody production; phase 2 study; phase II trial; pre-clinical; preclinical development; preclinical study; prevent; reproductive tract; response; satisfaction; sex; side effect; sperm cell; unintended pregnancy; uptake; vaginal fluid

Project Summary: Nearly half of all pregnancies in the U.S. are unintended, and most occur in women who are not using contraceptives. There are diverse reasons for not using contraceptives; one common reason is that many women have a strong aversion to using exogenous hormones due to real or perceived side effects as well as medical contraindications. It is likely that contraceptive use and satisfaction would substantially increase if there were a non-hormonal, user-controlled contraceptive method that did not require use immediately prior to intercourse, nor daily dosing. We believe we can create such a non-hormonal contraceptive based on vaginal delivery of an anti-sperm monoclonal antibody (mAb) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. This strategy, based on vaginal delivery of anti-sperm Ab, was validated in animal models in the 1980’s-90’s, and, unlike contraceptive vaccines, enables consistently reliable contraception and rapid reversibility. However, this strategy was not practical until recently due to the high costs of mAb production, and modest agglutination potencies of prior anti-sperm IgGs. We have developed a highly multivalent IgG, MM008, that targets a well-characterized and validated contraceptive antigen universally present on all human sperm. MM008 is highly homogeneous and stable, and can be produced at very high yields using conventional biomanufacturing processes. More importantly, MM008 is exceptionally potent, possesing >16-fold greater sperm-agglutinaton potency than the best anti-sperm IgG known in the literature. MM008 aggulutinates sperm even down to <100 ng/mL, and can reduce progressively motile sperm by 99.9% in the sheep vagina within 2 mins, at a dose of just 33 ug per sheep. Furthermore, we have shown that we can steadily release MM008 from a proprietary capsule-IVR system that sustains highly effective concentrations of MM008 in the sheep vagina for over 20 days (more than adequate to cover the fertility window in most women). We have also created vaginal film formulations of highly multivalent IgG mAbs that achieved complete agglutination of all sperm within 2 mins in sheep. These highly promising results motivated us to actively advance MM008 into the clinic. In this proposal, we seek to respond to the RFA HD- 22-018, and develop a highly sensitive and quantitative detection assay for measuring MM008 concentrations in a variety of biological matrices relevant for IND-enabling and clinical studies. In Specific Aim 1, we will establish a sandwich ELISA assay using a panel of anti-idiotype (anti-ID) Fabs against MM008. In Specific Aim 2, we will further optimize and qualify the assays to quantify MM008 in matrices including human serum, human cervicovaginal mucus, human mid-cycle endocervical mucus, and rat serum. These assays are part of the critical path for advancing MM008 through IND-enabling GLP studies and early clinical studies. Successful completion of the proposed work will accelerate our efforts to advance MM008 into the clinic.

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