METHODS FOR REDUCING IgG ANTIBODY TRANSFER FROM MOTHER TO UNBORN BABY DURING IMMUNOTHERAPY

Abstract

The specification discloses methods for treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects, or for preventing or attenuating increased disease activity due to adverse pregnancy outcome, methods for treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on their breastfeeding baby, methods for treating a disease in a non-pregnant subject of childbearing age in need thereof, methods for reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, or for reducing likelihood and extent of unwanted effects on a baby fed by a breastfeeding subject in need thereof, and methods for preventing or minimizing FcRn-dependent active transport of a human or humanized IgG antibody directed to a therapeutic target from a pregnant subject to her unborn baby or from a breastfeeding subject to a baby.

Description

METHODS FOR REDUCING IqG ANTIBODY TRANSFER FROM MOTHER TO UNBORN BABY DURING IMMUNOTHERAPY

[0001] This application is an international patent application that claims the benefit of priority and is entitled to the filing date pursuant to Article 8 of the Patent Cooperation Treaty (PCT) of U.S. Provisional Patent Application 63 / 500,687, filed May 8, 2023, the content of which is hereby incorporated by reference in its entirety.

[0002] Submitted as part of this patent application is a Sequence Listing filed as a XML file named UEIBC1-0017WO-SeqList_ST26.xml having a file size of 150,000 bytes and generated on May 8, 2024, the content of which is hereby expressly incorporated by reference in its entirety.FIELD

[0003] The present invention relates in general to the field of immunotherapy of women who are pregnant or breastfeeding an infant.BACKGROUND

[0004] The placenta is a highly specialized, vascular organ that receives blood supplies from both the maternal and the fetal systems and plays an essential role in fetal development, maternal adaptation, and maintenance of fetal and maternal health during pregnancy. Creating a vasculosyncytial barrier between maternal and fetal environments, the placenta serves as the interface responsible for facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, protects the fetus from infections and other maternal disorders, assists in the development of the fetal immune system, and is an important endocrine organ, producing hormones and growth factors that regulate both maternal and fetal metabolism and physiology. A highly ramified composite structure comprising epithelial syncytiotrophoblast and fetal capillary endothelium, the vasculosyncytial barrier (also known as the placental barrier) selectively controls the exchange of material between maternal and fetal blood. Although passive diffusion is sufficient to transport gases, urea, and small lipophilic solutes across the vasculosyncytial barrier, the vast majority of maternal-fetal exchange occurs by receptor mediated active transport system.

[0005] The neonatal Fc receptor (FcRn) is one such receptor-mediated transplacental transport system. This MHC class l-related receptor is the primary transporter of maternal immunoglobulin G (IgG) antibodies across the vasculosyncytial barrier of the placenta and provides the fetus withpassive protective humoral immunity. Beginning as early as 13 weeks of gestation, and increasing linearly throughout the pregnancy, FcRn mediates transfer of IgG antibodies provide protection to the fetus in utero. In addition, the maternal-fetal FcRn mediated transfer of IgG antibodies is central to neonatal immunity because these antibodies are not produced by the neonate at sufficient levels for nearly one year after birth. FcRn also mediates transfer of IgG antibodies to maternal milk during lactation, thereby supplementing passive immunity in breastfeeding newborns, making maternal IgG antibodies the principal mechanism of long-term humoral immunity for the infant during this vulnerable period of life.

[0006] While generally the use of therapeutic antibodies in pregnant women is undesired, in some cases, such as an advanced stage of cancer or chronic inflammatory disease, it can be inevitable for life-saving purposes. At the same time, the effect of immune modulating antibody-mediated drugs that pass through the placenta may have a detrimental effect for embryonic and fetal development, leading to impairments and / or miscarriage (Andrikopoulou et al, Immune Checkpoint Inhibitor Administration during Pregnancy: A Case Series, ESMO open 6: 100262, 2021). As such, women of childbearing age in need of immunotherapy may be reluctant to initiate such treatment due to concerns of safety to a possible pregnancy, whether desired or accidental. The failure to initiate immunotherapy in face of pregnancy may exacerbate the disease for which the immunotherapy is intended, and therefore the use of a variant IgG antibody as defined herein instead of a known IgG antibody will prevent increased disease activity due to adverse outcome of potential pregnancy.

[0007] For pregnant, breastfeeding, and non-pregnant women of childbearing age receiving immunotherapy, there remains an unmet need for reducing unwanted effects of antibody treatment on the women, their unborn baby, and their breastfeeding babies. Therefore, the use of a variant IgG antibody as disclosed herein instead of a known IgG antibody for such immunotherapies will prevent increased disease activity due to adverse outcome of potential pregnancySUMMARY

[0008] In an aspect, the present specification provides IgG antibody variants comprising one or more heavy chains having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as its variant version. In some aspects, an IgG antibody variant is a human IgG antibody variant or a humanized IgG antibody variant.

[0009] In an aspect, the present specification provides methods of treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the disease is treatable with a composition comprising an IgG antibody directed to a therapeutic target forthe disease. In some aspects, the disclosed methods comprise administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein that reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In this way, the disclosed methods protect the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject.

[0010] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0011] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0012] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament for treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0013] In an aspect, the present specification provides methods of preventing or attenuating increased disease activity in a pregnant subject in need thereof due to an adverse pregnancy outcome to an unborn baby, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease. In some aspects, the disclosed methods comprise administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgGantibody variant disclosed herein from the pregnant subject to the unborn baby. In this way, the disclosed methods protect the unborn baby from unwanted exposure to the IgG antibody variant disclosed herein while effectively preventing increased disease activity in the pregnant subject due to adverse pregnancy outcome.

[0014] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0015] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0016] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0017] In an aspect, the present specification provides methods of treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease. In some aspects, the disclosed methods comprise administering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In this way, the disclosed methods protect the breastfeeding baby from unwanted exposure to the IgG antibody variant disclosed herein while effectively treating the disease in the breastfeeding subject.

[0018] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibodyvariant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0019] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0020] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament for treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0021] In an aspect, the specification provides methods of treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease, and wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception. In some aspects, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a neurodegenerative disease, disorder, or condition. In some aspects, the disclosed methods comprise administering to the non-pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject across the placenta to the unborn baby. In this way, the disclosed methods protect the unborn baby from unwanted exposure to the IgG antibody variant disclosed herein while effectively treating the disease in the non-pregnant subject due to adverse pregnancy outcome.

[0022] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnantsubject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0023] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0024] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease, thereby if the non- pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0025] In an aspect, the specification provides methods of treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease, and wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby. In some aspects, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a neurodegenerative disease, disorder, or condition. In some aspects, the disclosed methods comprise administering to the non-pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target for the disease, thereby if the non- pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject across the placenta to the unborn baby. In this way, the disclosed methods protect the unborn baby from unwanted exposure to the IgG antibody variant disclosed herein while effectively treating the disease and preventing increased disease activity in the non-pregnant subject due to adverse pregnancy outcome.

[0026] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0027] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0028] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0029] In an aspect, the specification provides methods of reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease. In some aspects, the disclosed methods comprise administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In this way, the disclosed methods reduce unwanted effects on the unborn baby, and / or prevent or minimize the likelihood of miscarriage in the pregnant subject.

[0030] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0031] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0032] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0033] In an aspect, the specification provides methods of reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease. In some aspects, a disclosed method comprises administering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In this way, the disclosed methods reduce the likelihood and extent of unwanted effects on the breastfeeding baby fed by the breastfeeding subject.

[0034] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0035] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0036] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0037] In an aspect, the present specification provides method of preventing or minimizing FcRn- dependent active transport of an IgG antibody from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is afflicted with a disease that is treatable with an IgG antibody directed to a therapeutic target for the disease. In some aspects, a disclosed method comprises administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In this way, the disclosed methods prevent or minimize FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0038] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use preventing or minimizing FcRn-dependent active transport of an IgG antibody from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby.

[0039] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in preventing or minimizing FcRn-dependent active transport of an IgG antibody directed to a therapeutic target from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby.

[0040] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or minimizing FcRn-dependent active transport of an IgG antibody directed to a therapeutic target from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0041] In an aspect, the present specification provides method for preventing or minimizing FcRn- dependent active transport of an IgG antibody directed to a therapeutic target from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is afflicted with a disease that is treatable with an IgG antibody directed to a therapeutic target for the disease. In some aspects, a disclosed method comprises administering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces an FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In this way, the disclosed methods prevent or minimize FcRn-dependent active transport of the IgG antibody variant disclosed herein directed to a therapeutic target from the breastfeeding subject to the breastfeeding baby

[0042] In another aspect, the present specification provides a composition comprising an IgG antibody variant disclosed herein for use preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0043] In yet another aspect, the present specification provides use of a composition comprising an IgG antibody variant disclosed herein in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0044] In still another aspect, the present specification provides use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIGS. 1A-1 B are graphs of placental permeability of anti-PD-L1 antibody variants in mice using C57BL / 6J dams (age ~11 weeks, day 17 of pregnancy) with FIG. 1A showing serum levels of antibody in mice injected with a surr_nullanti-PD-L1 antibody variant; and FIG. 1 B showing serum levels of antibody in mice injected with a surr_null-H310A anti-PD-L1 antibody variant. Serum concentrations (M; Molar) of individual (X-axis) dams (n=1) and respective embryos (n=5-6) were measured 24 hours following injection using rELISA.

[0046] FIG. 2 is a graph of serum antibody placental penetration of anti-PD-L1 antibody variants with values quantified as the percentage ratio between the embryos and their corresponding dam. Margins represent mean ± s.e.m, where relevant. ***, p-value < 0.001 ; Student T-test.DETAILED DESCRIPTION

[0047] Immune checkpoints serve as critical regulators of the immune system, maintaining balance and tolerance to self and foreign antigens. In various pathological conditions such as cancer, chronic neurodegenerative diseases or autoimmune diseases, dysregulation of immune checkpoints can occur. This dysregulation often leads to either immune suppression, hindering the body's ability to mount effective immune responses against diseased cells or tissues, or overstimulation that may be destructive to the tissue.

[0048] The concept of immune checkpoint blockade involves selectively targeting these regulatory pathways to restore immune function. By targeting specific checkpoint molecules in cases of immune suppression, it is possible to unleash the body's immune response, promoting the infiltration of immune cells into diseased sites and facilitating tissue repair. In the cases of immune overstimulation, targeting specific checkpoints can restore regulation to an uncontrolled and undesired immune response. Immune checkpoint molecules can be categorized as either "negative regulators" or "positive regulators." Negative regulators act as “brakes” or “off switches” on the immune response and blockade of a negative regulator activates the immune system. Positive regulators act as “on switches” on the immune response and stimulation of a positive regulator activates the immune system.

[0049] Modified variants based on antibodies raised against the immune checkpoint molecule PD-L1 were designed and developed with unique biological properties in order to support the mechanism of action needed for treatment of neurodegenerative diseases, see US Patents 10,995,141 and 1 1 ,732,046, the content of each being hereby incorporated by reference in its entirety. Specifically, these modified anti-PD-L1 antibody variants contains, in addition to other mutations, a single point mutation (designated H310A) in its hlgG 1 Fc region that blocks Fc binding to the neonatal Fc receptor (FcRn). This H310A modification effectively increased the clearance rate of the antibody from the circulation, resulting in a better safety profile in terms of potential risk for inducing autoimmune-related adverse events (Baruch, et al., IBC-Ab002, an anti-PD-L1 monoclonal antibody tailored for treating Alzheimer’s disease. Alzheimer’s Dement. 16: e042978, 2020).

[0050] The IgG Fc domain has the capacity to interact with diverse types of receptors, including the FcRn and Fey receptors (FcyRs), which confer pleiotropic biological activities. Whereas FcRnregulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by FcyRs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. FcRn interacts with the heavy chain of IgG antibodies at the interface between the CH2 and CH3 domains of the Fc portion in a pH-dependent mannerwhich protects the antibodies from intracellular degradation. This property permits FcRn to efficiently transport the IgG from the intestinal lumen by endocytosis (low pH, binding state) to the extracellular space (neutral pH, release state).

[0051] As shown in Example 1 , antibodies for immune checkpoints lacking FcRn activity have unexpectedly demonstrated a reduction in placental permeability. These findings indicate that such antibody variants provide an enhanced safety profile in the treatment of a disease in a woman who is pregnant with a child or breast feeding an infant where such treatment may be harmful to the unborn baby or infant, as well as providing prophylactic care to a woman of childbearing age undergoing treatment for a disease where there is a possibility of conception. In addition, because this FcRn-IgG Fc domain internation is conversed across all IgG antibodies, the disclosed protocol for making an IgG antibody variant disclosed herein and the employment of these antibody variants in the disclosed methods and uses will be applicable to any therapeutic IgG antibody and not just antibodies raised against an immune checkpoint molecule. In view of the unexpected results described above, the present specification provides treatment methods and uses that rely on modified IgG antibodies that lack or have reduced binding affinity to an FcRn while maintaining therapeutic efficacy for disease modification. As such, a woman of childbearing age who may be reluctant to initiate an immunotherapy due to safety concerns of a current or possible pregnancy or a breastfeeding baby will now have a safe and effect immunotherapy without any undue risk to the unborn or breastfeeding baby. In this way, both the woman will receive the beneficial effect of an immunotherapy for a disease she is suffering from while at the same time have comfort in knowing that any adverse outcome to her potential pregnancy, pregnancy, or breastfeeding baby will be minimized.

[0052] A treatment method and use disclosed herein is implemented with an IgG antibody directed to a therapeutic target for the disease. Antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical immunoglobulin heavy (H) chains and two identical immunoglobulin light (L) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges, whereas each light chain has a variable domain at the amino-terminus followed by a single constant domain.

[0053] There are five types of mammalian immunoglobulin heavy chain: gamma (y), delta (5), alpha (a), mu (p) and epsilon (E), each defining a class of immunoglobulins: IgG, IgD, IgA, IgM and IgE, respectively. Heavy chains IgG and IgA have approximately 450 amino acids while heavy chains IgM and IgE have approximately 550 amino acids. Each heavy chain comprises a constant region and a variable region. A constant region is the same for all immunoglobulins of the same class but differs between classes. Each heavy chain has a variable region comprising a variable domain (VH) at the amino-terminus followed by a constant region comprising a number of constant domains. Heavy chains IgG, IgD, and IgA have a constant region composed of three tandem immunoglobulin domains (CH1 , CH2 and CH3) and have a hinge region for added flexibility. Heavy chains IgM and IgE have a constant region composed of four tandem immunoglobulin domains (CH1 , CH2, CH3 and CH4). The variable region of the heavy chain differs between different antibodies producing B cells but is the same for all immunoglobulins produced by the same B cell or B cell clone. The variable domain is composed of a single immunoglobulin domain.

[0054] There are two types of mammalian immunoglobulin light chains: the kappa (K) chain and the lambda (A) chain. The lambda class has four subtypes A1 , A2, A3, and A4. Only one type of light chain is present in a typical antibody, thus the two light chains of an individual antibody are identical. The approximate length of a light chain is from 21 1 to 217 amino acids. Each light chain is composed of two tandem immunoglobulin domains, a variable domain (VL) at the amino-terminus followed by a constant domain. The variable domain is important for binding antigen and the constant domain determines the light chain type, i.e., kappa or lambda). The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.

[0055] The complete antigen-recognition and antigen-binding site is contained within the variable domains of the antibody. This site includes a dimer of one heavy chain variable domain (VH) and one light chain variable domain (VL) in tight, non-covalent association. Each domain comprises four framework regions (FR), which largely adopt a p-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases form part of, the p-sheet structure. Each hypervariable region comprises an amino acid sequence corresponding to a complementarity determining region (CDRs). Collectively, it is the three-dimensional configuration of the six CDR regions that define an antigen-binding site on the surface of the VH-VL dimmer that confers antigen-binding specificity. See e.g., Cyrus Chothia, et al., Conformations of Immunoglobulin Hypervariable Regions, Nature 342(6252): 877-883 (1989); Elvin A. Kabat, et al Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), each of which is incorporated by reference in its entirety. The constantdomains of the antibody are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity.

[0056] Aspects of the present disclosure comprise, in part, an IgG antibody variant. As used herein, the terms “an IgG antibody variant” and “a variant version of an IgG antibody” refer to an IgG antibody in which the light and heavy chains have one or more amino acid substitutions in an Fc region that reduces or eliminates binding affinity of the IgG antibody variant to a neonatal Fc receptor (FcRn) relative to the IgG antibody lacking the one or more amino acid modifications. The IgG antibody lacking the one or more amino acid modifications is a reference antibody, also referred to herein as an unaltered or original IgG antibody and refers solely to the amino acid sequence at the lgG1 Fc region that mediates Fc binding to the FcRn. Except for the one or more amino acid substitutions in a Fc region that reduces or eliminates binding affinity to a neonatal Fc receptor, the variant version and the reference antibody of an IgG antibody have identical amino acid sequences. In aspects of these embodiments, an IgG antibody variant and its corresponding reference IgG antibody can be an IgG 1 antibody, an lgG2 antibody, an lgG3 antibody, or an lgG4 antibody. In aspects of these embodiments, an IgG antibody variant and its corresponding reference IgG antibody is a therapeutic IgG antibody directed to a therapeutic target.

[0057] In some embodiments, an IgG antibody variant disclosed herein, and its corresponding reference IgG antibody, is a human IgG antibody. The term “human IgG antibody”, also known as “fully human IgG antibody” as used herein refers to IgG antibodies having human-sequence derived CDR regions. A human IgG antibody is typically developed in transgenic mice genetically engineered with the human immunoglobulin locus (Mallbris et al., Molecular Insights into Fully Human and Humanized Monoclonal Antibodies, J. Clin. Aesthet. Dermatol. 9(7): 13-15, 2016). In aspects of these embodiments, a human IgG antibody is a human lgG1 , a human lgG2, a human lgG3, or a human lgG4. In aspects of these embodiments, a human IgG antibody variant and its corresponding reference IgG antibody is a therapeutic human IgG antibody directed to a therapeutic target.

[0058] In some embodiments, an IgG antibody variant disclosed herein, and its corresponding reference IgG antibody, is a humanized IgG antibody. The term “humanized IgG antibody” as used herein refers to IgG antibodies having non-human-sequence derived CDR regions, typically mice, rats, hamsters, and chickens. As an example, a humanized IgG antibody can be generated in wild-type mice bearing the mouse immunoglobulin locus that has been modified to increase the amino acid similarity to an antibody produced naturally in humans. (Mallbris et al., Molecular Insights into Fully Human and Humanized Monoclonal Antibodies, J. Clin. Aesthet. Dermatol. 9(7):13-15, 2016). In aspects of these embodiments, a humanized IgG antibody is a humanized IgG 1 , a humanized lgG2, a humanized lgG3, or a humanized lgG4. In aspects of these embodiments, a humanized IgG antibody variant and its corresponding reference IgG antibody is a therapeutic humanized IgG antibody directed to a therapeutic target.

[0059] The term “Fc-related effector function” as used herein refers e.g., to antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complementdependent cytotoxicity (GDC) (see e.g., Van der Horst et al., Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies, Cancers (Basel) 12(10): 3041 , 2020). In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, comprises a heavy chain constant domain (CH) that lack Fc-related effector function. In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, comprises a heavy chain constant domain (CH) which lacks cytotoxicity. In aspects of these embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, comprises a heavy chain constant domain (CH) which lacks antibody dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxic activity (CDC) and / or antibody dependent cellular phagocytosis (ADCP).

[0060] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid deletions, additions or substitutions located in a Fc region that reduces binding affinity of the IgG antibody variant to an FcRn relative to the reference IgG antibody lacking the one or more amino acid deletions, additions, or substitutions. In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid deletions, additions or substitutions located in the CH2 domain and / or CH3 domain that reduces binding affinity of the IgG antibody variant to an FcRn relative to the reference IgG antibody lacking the one or more amino acid deletions, additions or substitutions. In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising 1 , 2, 3, 4 or 5 amino acid deletions, additions or substitutions located in the CH2 domain and / or CH3 domain that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid deletions, additions or substitutions.

[0061] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has reduced binding affinity to an FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. Binding affinity refers to the length of time the antibody resides at its FcRn binding site and can be viewed as the strength with which an antibody binds to the FcRn. Binding affinity can be described as an antibody’s equilibrium dissociation constant (KD), which is defined as the ratio Kd / Ka at equilibrium. Where Ka is the antibody’s association rate constant, and Kd is the antibody’s dissociation rate constant. Binding affinity is determined by both the association and the dissociation and alone neither high association nor low dissociation can ensure high affinity. The association rate constant (Ka), or on-rate constant (Kon), measures the number of binding events per unit time, or the propensity of the antibody and the FcRn to associate reversibly into its antibody-FcRn complex. The association rate constant is expressed in M-1 s-1 and is symbolized as follows: [Ab] x [FcRn] x Kon. The larger the association rate constant, the more rapidly the antibody binds to the FcRn, or the higher the binding affinity between antibody and the FcRn. The dissociation rate constant (Kd), or off-rate constant (Koff), measures the number of dissociation events per unit time propensity of an antibody-FcRn complex to separate (dissociate) reversibly into its component molecules, namely the antibody and the FcRn. The dissociation rate constant is expressed in s-1 and is symbolized as follows: [Ab + FcRn] x Koff. The smaller the dissociation rate constant, the more tightly bound the antibody is to the FcRn, or the higher the binding affinity between antibody and FcRn. The equilibrium dissociation constant (KD) measures the rate at which new antibody-FcRn complexes formed equals the rate at which antibody-FcRn complexes dissociate at equilibrium. The equilibrium dissociation constant is expressed in M and is defined as Koff / Kon=[Ab] x [FcRn] / [Ab + FcRn], where [Ab] is the molar concentration of the antibody, [FcRn] is the molar concentration of the FcRn, and [Ab + FcRn] is the of molar concentration of the antibody-FcRn complex, where all concentrations are of such components when the system is at equilibrium. The smaller the equilibrium dissociation constant, the more tightly bound the antibody is to the FcRn, or the higher the binding affinity between antibody and FcRn. Methods for measuring affinity are well-known in the art and are described for example in Jarmoskaite, et al., How to measure and evaluate binding affinities, Elife 9:e57264 (2020).

[0062] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a low association rate constant for FcRn. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an association rate constant for FcRn of, e.g., less than 1 x 10° M1s1, less than 1 x 101M1s1, lessthan 1 x 102M1s1, less than 1 x 103M1s1, less than 1 x 104M1s1, or less than 1 x 105M1S’1. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an association rate constant for FcRn of, e.g., more than 1 x 10° M1s1, more than 1 x 101M1s1, more than 1 x 102M’1S’1, more than 1 x 103M’1S’1, more than 1 x 104M1S’1, or more than 1 x 105M’1S’1. In yet other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an association rate constant for FcRn of between 1 x 10° M’1S’1to 1 x 101M’1S’1, 1 x 10° M’1s-1to 1 x 102M’1S’1, 1 x 10° M’1S’1to 1 x 103M’1S’1, 1 x 10° M’1s1to 1 x 104M’1s1, 1 x 10° M’1s1to 1 x 105M’1S’1, 1 x 101M’1S’1to 1 x 102M’1S’1, 1 x 101M’1s1to 1 x 103M’1s1, 1 x 101M’1s1to 1 x 104M’1S’1, 1 x 101M’1S’1to 1 x 105M’1S’1, 1 x 102M’2s1to 1 x 103M’1s1, 1 x 102M’1s1to 1 x 104M’1S’1, 1 x 102M’1S’1to 1 x 105M’1S’1, 1 x 103M’1s1to 1 x 104M’1s1, 1 x 103M’1s1to 1 x 105M’1S’1, or 1 x 104M’1S’1to 1 x 105M’1s1.

[0063] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a lower association rate constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an association rate constant for FcRn that is, e.g., at least 1 x 101-fold less, at least 1 x 102-fold less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105-fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an association rate constant for FcRn that is between, e.g., 1 x 101to 1 x 102-fold less, 1 x 101to 1 x 103-fold less, 1 x 101to 1 x 104- fold less, 1 x 101to 1 x 105-fold less, 1 x 101to 1 x 106-fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 108-fol d less, 1 x 102to 1 x 103-fold less, 1 x 102to 1 x 104-fold less, 1 x 102to 1 x 105- fold less, 1 x 102to 1 x 106-fold less, 1 x 102to 1 x 107-fold less, 1 x 102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x 106-fold less, 1 x 103to 1 x 107- fold less, 1 x 103to 1 x 108-fold less, 1 x 104to 1 x 105-fold less, 1 x 104to 1 x 106-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107- fold less, 1 x 105to 1 x 108-fold less, 1 x 106to 1 x 107-fold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the oneor more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0064] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a high dissociation rate constant for FcRn. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a dissociation rate constant for FcRn of, e.g., less than 1 x 105s1, less than 1 x 106s1, less thanI x 10 '" s '1, less than 1 x 108s1, less than 1 x 109s1, less than 1 x 1010s1, or less than 1 x 10-I IS’1. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a dissociation rate constant for FcRn of, e.g., more than 1 x 105s1, more than 1 x 106s1, more than 1 x 10-7s1, more than 1 x 10ss1, more than 1 x 109s1, more than 1 x 1010s1, or more than 1 x I O11s1. In yet other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a dissociation rate constant for FcRn of between, e.g., 1 x 105s1to 1 x 106s1, 1 x 10-5s-1to 1 x 10-7s-1, 1 x 10-5s-1to 1 x 10-8s-1, 1 x 10-5s1to 1 x 109s1, 1 x 105s1to 1 x 1010s-1, 1 x 10-5s-1to 1 x 10-11s-1, 1 x 10-6S’1to 1 x 10-7s-1, 1 x 106s1to 1 x 108s1, 1 x 106s1to 1 x 10-9s-1, 1 x 106s-1to 1 x 10-1° s-1, 1 x 106S’1to 1 x 1011s1, 1 x 107s1to 1 x 108s1, 1 x 107s1to 1 x 109s1, 1 x 107s1to 1 x 1010s1, 1 x 107s1to 1 x 1011s1, 1 x 108s1to 1 x 109s1, 1 x 108s1to 1 x 1010s1, 1 x 108s1to 1 x 1011s1, 1 x 109s1to 1 x 101° s1, 1 x 109s1to 1 x 1011S’1, or 1 x 10‘10S’1to 1 x 1011S’1.

[0065] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a higher dissociation rate constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a dissociation rate constant for FcRn that is, e.g., at least 1 x 101-fold more, at least 1 x 102-fold more, at least 1 x 103-fold more, at least 1 x 104-fold more, at least 1 x 105-fold more, at least 1 x 106-fold more, at least 1 x 107-fold more, or at least 1 x 108-fold more, than the dissociation rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a dissociation rate constant for FcRn that is between, e.g., 1 x 101to 1 x 102-fold more, 1 x 101to 1 x 103-fold more, 1 x 101to 1x 104-fold more, 1 x 101to 1 x 105-fold more, 1 x 101to 1 x 106-fold more, 1 x 101to 1 x 107-fold more, 1 x 101to 1 x 108-fold more, 1 x 102to 1 x 103-fold more, 1 x 102to 1 x 104-fold more, 1 x102to 1 x 105-fold more, 1 x 102to 1 x 10s-fold more, 1 x 102to 1 x 107-fold more, 1 x 102to 1 x108-fold more, 1 x 103to 1 x 104-fold more, 1 x 103to 1 x 105-fold more, 1 x 103to 1 x 10s-fold more, 1 x 103to 1 x 107-fold more, 1 x 103to 1 x 108-fold more, 1 x 104to 1 x 105-fold more, 1 x104to 1 x 10s-fold more, 1 x 104to 1 x 107-fold more, 1 x 104to 1 x 108-fold more, 1 x 105to 1 x106-fold more, 1 x 105to 1 x 107-fold more, 1 x 105to 1 x 108-fold more, 1 x 106to 1 x 107-fold more, 1 x 106to 1 x 108-fold more, 1 x 107to 1 x 108-fold more, than the dissociation rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0066] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a low equilibrium dissociation constant for FcRn. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an equilibrium dissociation constant for FcRn of, e.g., less than 1 pM, less than 10 pM, less than 100 pM, less than 1 mM, less than 10 mM, or less than 100 mM. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an equilibrium dissociation constant for FcRn of, e.g., more than 1 pM, more than 10 pM, more than 0100 pM, more than 1 mM, more than 10 mM, or more than 100 mM. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an equilibrium dissociation constant for FcRn of between, e.g., 1 pM to 10 pM, 1 pM to 100 pM, 1 pM to 1 mM, 1 pM to 10 mM, 1 pM to 100 mM, 10 pM to 100 pM, 10 pM to 1 mM, 10 pM to 10 mM, 10 pM to 100 mM, 100 pM to 1 mM, 100 pM to 10 mM, 100 pM to 100 mM, 1 mM to 10 mM, 1 mM to 100 mM, or 10 mM to 100 mM.

[0067] In some embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a lower equilibrium dissociation constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an equilibrium dissociation constant for FcRn that is, e.g., at least 1 x 101-fold less, at least 1 x 102-fold less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105-fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the equilibrium dissociation constant of an IgG antibody that lacks the one or more amino acid modifications ofthe IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In other aspects of these embodiments, the binding affinity of an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has an equilibrium dissociation constant for FcRn that is between, e.g., 1 x 101to 1 x 102-fold less, 1 x101to 1 x 103-fold less, 1 x 101to 1 x 104-fold less, 1 x 101to 1 x 105-fold less, 1 x 101to 1 x 106- fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 108-fold less, 1 x 102to 1 x 103-fold less, 1 x102to 1 x 104-fol d less, 1 x 102to 1 x 105-fo Id less, 1 x 102to 1 x 106-fold less, 1 x 102to 1 x 107- fold less, 1 x 102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x 106-fold less, 1 x 103to 1 x 107-fold less, 1 x 103to 1 x 108-fold less, 1 x 104to 1 x 105- fold less, 1 x 104to 1 x 106-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107-fold less, 1 x 105to 1 x 108-fold less, 1 x 10® to 1 x ICTfold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 108-fo Id less, than the equilibrium dissociation constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0068] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, reduced binding affinity for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is, e.g., at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, or at least 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is, e.g., at most 10% less, at most 20% less, at most 30% less, at most 40% less, at most 50% less, at most 60% less, at most 70% less, at most 80% less, at most 90% less, or at most 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is between, e.g., about 10% to about 20% less, about 10% to about 30% less, about 10% to about 40% less, about 10% to about 50% less, about 10% to about 60% less, about 10% to about 70% less, about 10% to about 80% less, about 10% to about 90% less, about 10% to about 100% less, about 20% to about 30% less, about 20% to about 40%less, about 20% to about 50% less, about 20% to about 60% less, about 20% to about 70% less, about 20% to about 80% less, about 20% to about 90% less, about 20% to about 100% less, about 30% to about 40% less, about 30% to about 50% less, about 30% to about 60% less, about 30% to about 70% less, about 30% to about 80% less, about 30% to about 90% less, about 30% to about 100% less, about 40% to about 50% less, about 40% to about 60% less, about 40% to about 70% less, about 40% to about 80% less, about 40% to about 90% less, about 40% to about 100% less, about 50% to about 60% less, about 50% to about 70% less, about 50% to about 80% less, about 50% to about 90% less, about 50% to about 100% less, about 60% to about 70% less, about 60% to about 80% less, about 60% to about 90% less, about 60% to about 100% less, about 70% to about 80% less, about 70% to about 90% less, about 70% to about 100% less, about 80% to about 90% less, about 80% to about 100% less, or about 90% to about 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0069] In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is, e.g., at least 1 x 101-fold less, at least 1 x 102-fold less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105-fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is between, e.g., between, e.g., 1 x101to 1 x 102-fold less, 1 x 101to 1 x 103-fold less, 1 x 101to 1 x 104-fold less, 1 x 101to 1 x 1 enfold less, 1 x 101to 1 x 106-fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 108-fold less, 1 x102to 1 x 103-fol d less, 1 x 102to 1 x 104-fold less, 1 x 102to 1 x 105-fold less, 1 x 102to 1 x 106- fold less, 1 x 102to 1 x 107-fold less, 1 x 102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x 106-fold less, 1 x 103to 1 x 107-fold less, 1 x 103to 1 x 108- fold less, 1 x 104to 1 x 105-fold less, 1 x 104to 1 x 106-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107-fold less, 1 x 105to 1 x 1 enfold less, 1 x 106to 1 x 107-fold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 1 O old less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0070] In some aspects, the disclosed methods comprise administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, that has reduced binding affinity to an FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. Due to the relatively reduced binding affinity of the IgG antibody variant disclosed herein, its FcRn-dependent active transport from the pregnant subject to the unborn baby is reduced. FcRn-dependent active transport is readily measured in mice as is described e.g. in Example 1 below and can be used as a surrogate marker for affinity. This is done by using a mice IgG antibody variant that mimics a human IgG antibody variant or a humanized IgG antibody variant altered at only one amino acid residue as compared to a mouse IgG antibody that lacks the one amino acid modification of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0071] For example, reduced FcRn-dependent active transport exhibited in a mice IgG antibody variant that mimics a human IgG antibody variant or a humanized IgG antibody variant altered at only one amino acid residue as compared to a mouse IgG antibody that lacks the one amino acid modification of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant indicates that the affinity of the mice IgG antibody variant, and therefore also the human IgG antibody variant or a humanized IgG antibody variant, is reduced.

[0072] Thus, in aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby that is, e.g., 0% or less than 0.1 %, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1%, less than 1.1 %, less than 1.2%, less than 1.3%, less than 1.4%, less than 1.5%, less than 1.6%, less than 1.7%, less than 1.8%, less than 1.9%, less than 2%, less than 2.1 %, less than 2.2%, less than 2.3%, less than 2.4%, less than 2.5%, less than 2.6%, less than 2.7%, less than 2.8%, less than 2.9%, less than 3%, less than 3.1%, less than 3.2%, less than 3.3%, less than 3.4%, less than 3.5%, less than 3.6%, less than 3.7%, less than 3.8%, less than 3.9%, less than 4%, less than 4.1 %, less than 4.2%, less than 4.3%, less than 4.4%, less than 4.5%, less than 4.6%, less than 4.7%, less than 4.8%, less than 4.9%, less than 5%, less than 5.1 %, less than 5.2%, less than 5.3%, less than 5.4%, less than 5.5%, less than 5.6%, less than 5.7%, less than 5.8%, less than 5.9%, less than 6%, less than 6.1%, less than 6.2%, less than 6.3%, less than 6.4%, less than 6.5%, less than 6.6%, less than 6.7%, less than 6.8%, less than 6.9%, less than 7%, less than 7.1 %, less than 7.2%, less than 7.3%, less than 7.4%, less than 7.5%, less than 7.6%, less than 7.7%, less than 7.8%, less than 7.9%, less than 8%, less than 8.1 %, less than 8.2%,less than 8.3%, less than 8.4%, less than 8.5%, less than 8.6%, less than 8.7%, less than 8.8%, less than 8.9%, less than 9%, less than 9.1%, less than 9.2%, less than 9.3%, less than 9.4%, less than 9.5%, less than 9.6%, less than 9.7%, less than 9.8%, less than 9.9%, or less than 10% of the FcRn-dependent transport of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0073] In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby that is, e.g., 0% or less than 0.1%, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1 %, less than 1.1 %, less than 1.2%, less than 1.3%, less than 1.4%, less than 1.5%, less than 1.6%, less than 1.7%, less than 1.8%, less than 1.9%, less than 2%, less than 2.1 %, less than2.2%, less than 2.3%, less than 2.4%, less than 2.5%, less than 2.6%, less than 2.7%, less than2.8%, less than 2.9%, less than 3%, less than 3.1 %, less than 3.2%, less than 3.3%, less than3.4%, less than 3.5%, less than 3.6%, less than 3.7%, less than 3.8%, less than 3.9%, less than4%, less than 4.1 %, less than 4.2%, less than 4.3%, less than 4.4%, less than 4.5%, less than 4.6%, less than 4.7%, less than 4.8%, less than 4.9%, less than 5%, less than 5.1 %, less than5.2%, less than 5.3%, less than 5.4%, less than 5.5%, less than 5.6%, less than 5.7%, less than5.8%, less than 5.9%, less than 6%, less than 6.1 %, less than 6.2%, less than 6.3%, less than6.4%, less than 6.5%, less than 6.6%, less than 6.7%, less than 6.8%, less than 6.9%, less than7%, less than 7.1 %, less than 7.2%, less than 7.3%, less than 7.4%, less than 7.5%, less than 7.6%, less than 7.7%, less than 7.8%, less than 7.9%, less than 8%, less than 8.1 %, less than8.2%, less than 8.3%, less than 8.4%, less than 8.5%, less than 8.6%, less than 8.7%, less than8.8%, less than 8.9%, less than 9%, less than 9.1 %, less than 9.2%, less than 9.3%, less than9.4%, less than 9.5%, less than 9.6%, less than 9.7%, less than 9.8%, less than 9.9%, or less than 10% of the FcRn-dependent transport of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.

[0074] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid deletions, additions or substitutions in a Fc region at amino acid residue positions L234, L235, G236, S239, F243, K248, T250, M252, I253, S254, R255, T256, P257, H268, D270, E272, H285, K288, K290, P291 , R292, S298, Y300, V305, V308, L309, H310, Q31 1 , L314, K322, K326, A330, I332, E333, K334, D356,E357, L358, P396, S415, M428, H433, N434, H435, or Y436, or any combination thereof, the amino acid residue positions based on the EU numbering system generalized for all antibodies (Table 1). In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid substitutions in a Fc region at amino acid residue positions L234, L235, G236, S239, F243, K248, T250, M252, I253, S254, R255, T256, P257, H268, D270, E272, H285, K288, K290, P291 , R292, S298, Y300, V305, V308, L309, H310, Q311 , L314, K322, K326, A330, I332, E333, K334, D356, E357, L358, P396, S415, M428, H433, N434, H435, or Y436, or any combination thereof, the amino acid residue positions based on the EU numbering system generalized for all antibodies (Table 1).

[0075] In other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid substitutions at positions L234, L235, I253, T256, K288, H310, K322, S415, H433, H435, or Y436 or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L234, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L235, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position I253, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position T256, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K288, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H310, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K322, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position S415, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H433, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H435, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position Y436, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position L234, an amino acid substitution of A, C, W, or Y at position L235, an amino acid substitution of A, F, H, P, W, or Y at position I253, an amino acid substitution of D, E, K, N, Q, R, or S at position T256, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K288, an amino acid substitution of A, D, E, K, N, Q, R, or S at position H310, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K322, an amino acid substitution of A, D, E, K, N, Q, R, or T at position S415, an amino acid substitution of A, D, E, K, Q, R, S, T, or W at position H433, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H435, anamino acid substitution of A, D, E, K, Q, R, S, T, or W at position Y436, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In further aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A at position L234, an amino acid substitution of A at position L235, an amino acid substitution of I at position I253, an amino acid substitution of E at position T256, an amino acid substitution of A at position K288, an amino acid substitution of A, Q, or R at position H310, an amino acid substitution of A at position K322, an amino acid substitution of T at position S415, an amino acid substitution of A, Q, or R at position H433, an amino acid substitution of A, Q, or R at position H435, an amino acid substitution of A, Q, or R at position Y436, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0076] In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more substitution at positions L234, L235, H310, K322 and H435, or any combination thereof, (residue positions based on the Kabat numbering system generalized for all antibodies) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position 234, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position 235, an amino acid substitution of A, C, D, E, F,G, I, K, L, M, P, Q, R, S, T, V, or W at position 310, an amino acid substitution of A, C, D, F, G,H, I, L, M, N, P, S, T, V, W, or Y at position 322, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position 435, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position 234, an amino acid substitution of A, C, W,or Y at position 235, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position 310, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position 322, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position 435, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In still other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A at position 234, an amino acid substitution of A at position 235, an amino acid substitution of A at position 310, an amino acid substitution of A at position 322, an amino acid substitution of Q at position 435, or any combination thereof, (residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1) thereof that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0077] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid deletion, addition or substitution at position L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, or Y441 , or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising comprises 1 , 2, 3, 4 or 5 amino acid deletions, additions or substitutions at position L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, orY441 , or any combination thereof, (residue positions based on of IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid deletions, additions or substitutions.

[0078] In other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid substitutions at positions L239, L240, 1258, T261 , K293, H315, K327, S420, H438, H440, orY441 , or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L239, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L240, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position I258, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position T261 , an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K293, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K327, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position S420, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H438, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position Y441 ,or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position L239, an amino acid substitution of A, C, W, or Y at position L240, an amino acid substitution of A, F, H, P, W, or Y at position I258, an amino acid substitution of D, E, K, N, Q, R, or S at position T261 , an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K293, an amino acid substitution of A, D, E, K, N, Q, R, or S at position H315, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K327, an amino acid substitution of A, D, E, K, N, Q, R, or T at position S420, an amino acid substitution of A, D, E, K, Q, R, S, T, or W at position H438, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H440, an amino acid substitution of A, D, E, K, Q, R, S, T, or W at position Y441 ,or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In further aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constantdomain (CH) comprising an amino acid substitution of A at position L239, an amino acid substitution of A at position L240, an amino acid substitution of I at position 1258, an amino acid substitution of E at position T261 , an amino acid substitution of A at position K293, an amino acid substitution of A, Q, or R at position H315, an amino acid substitution of A at position K327, an amino acid substitution of T at position S420, an amino acid substitution of A, Q, or R at position H438, an amino acid substitution of A, Q, or R at position H440, an amino acid substitution of A, Q, or R at position Y441 ,or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0079] In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more substitution at positions L239, L240, H315, K327, or H440, or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L239, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L240, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K327, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position L239, an amino acid substitution of A, C, W, or Y at position L240, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H315, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K327, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H440, or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the sameamino acid substitutions. In still other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A at position L239 (L239A), an amino acid substitution of A at position L240 (L240A), an amino acid substitution of A at position H315 (H315A), an amino acid substitution of A at position K327 (K327A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof, (residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3) thereof that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0080] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid deletion, addition or substitution at position L235, L236, G237, S240, F244, K249, T251 , M253, I254, S255, R256, T257, P258, H269, D271 , E273, H286, K289, K291 , P292, R293, S299, Y301 , V306, V309, L310, H31 1 , Q312, L315, K323, K327, A331 , I333, E334, K335, D357, E358, L359, P397, S416, M429, H434, N435, H436, or Y437, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising comprises 1 , 2, 3, 4 or 5 amino acid deletions, additions or substitutions at position L235, L236, G237, S240, F244, K249, T251 , M253, I254, S255, R256, T257, P258, H269, D271 , E273, H286, K289, K291 , P292, R293, S299, Y301 , V306, V309, L310, H311 , Q312, L315, K323, K327, A331 , I333, E334, K335, D357, E358, L359, P397, S416, M429, H434, N435, H436, or Y437, or any combination thereof, (residue positions based on of IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid deletions, additions or substitutions.

[0081] In other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising one or more amino acid substitutions at positions L235, L236, I254, T257, K289, H31 1 , K323, S416, H434, H436, or Y437, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of thisembodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L235, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L236, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position I254, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position T257, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K289, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H31 1 , an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K323, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position S416, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H434, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H436, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position Y437,or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position 235, an amino acid substitution of A, C, W, or Y at position 236, an amino acid substitution of A, F, H, P, W, or Y at position 254, an amino acid substitution of D, E, K, N, Q, R, or S at position 257, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position 289, an amino acid substitution of A, D, E,K, N, Q, R, or S at position 31 1 , an amino acid substitution of A, D, G, H, M, N, P, S, or T at position 323, an amino acid substitution of A, D, E, K, N, Q, R, or T at position 416, an amino acid substitution of A, D, E, K, Q, R, S, T, or W at position 434, an amino acid substitution of C, D, E,K, Q, R, S, T, or W at position 436, an amino acid substitution of A, D, E, K, Q, R, S, T, or W at position 437, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In further aspects of this embodiment, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A at position L235, an amino acid substitution of A at position L236, an amino acid substitution of I at position I254, an amino acid substitution of E at position T256, an amino acid substitution of A at position K289, an amino acid substitution of A, Q, or R at position H311 , an amino acid substitution of A at position K323, an amino acid substitution of T at position S416, an amino acid substitution of A, Q, or R at position H434, an amino acid substitution of A, Q, or R at position H436, an amino acid substitution of A,Q, or R at position Y437,or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0082] In aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid one or more substitution at positions L235, L236, H311 , K323, or H436, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L235, an amino acid substitution of A, C, D, E, G, H, K, N, P,Q, R, S, T, W, or Y at position L236, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P,Q, R, S, T, V, or W at position H311 , an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P,S, T, V, W, or Y at position K323, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q,R, S, T, V, or W at position H436, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an lgG1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A, C, W, or Y at position L235, an amino acid substitution of A, C, W, or Y at position L236, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H31 1 , an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K323, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H436, or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibody variant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions. In still other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, includes an IgG 1 immunoglobulin heavy chain constant domain (CH) comprising an amino acid substitution of A at position L235 (L235A), an amino acid substitution of A at position L236 (L236A), an amino acid substitution of A at position H31 1 (H31 1A), an amino acid substitution of A at position K323 (K323A), an amino acid substitution of Q at position H436 (H436Q), or any combination thereof, (residue positions based on IgG heavy chain sequence SEQ ID NO: 4) that reduces binding affinity of the IgG antibodyvariant to an FcRn relative to a reference IgG antibody not containing the same amino acid substitutions.

[0083] In certain embodiments, the Fc region of the therapeutic antibody is an lgG1 or lgG3 Fc region comprising an Fc gamma receptor (FcyR)-binding domain that mediates ADCC or ADCP; or it is an IgG 1 or lgG3 Fc region comprising a binding domain to the complement protein C1 q and thus mediates activation of the classical pathway of the complement system leading to CDC (van der Horst et al., 2020).

[0084] In aspects of these embodiments, the FcRn-dependent active transport of an IgG antibody variant disclosed herein across the placenta or intestine is substantially undetectable due to reduced binding to the FcRn.

[0085] In some embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, comprises one or more additional amino acid substitutions in its Fc region that modify Fc-related effector function. In aspects of these embodiments, the one or more additional amino acid substitutions increases Fc-related effector function and is selected from S298A / E333A / K334A, S239D / I332E, S239D / A330L / I332E,G236A, G236A / S239D / I332E, G236A / A330L / I332E, G236A / S239D / A330L / I332E,F243L / R292P / Y300LA / 305I / P396L, and L235V / F243L / R292P / Y300L / P396L the amino acid residue positions based on the EU numbering system generalized for all antibodies (Table X), or any other combination; or a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on the EU numbering system generalized for all antibodies (Table X). In other aspects of these embodiments, the one or more additional amino acid substitutions increases Fc-related effector function and is selected from S303A / E338A / K339A, S244D / I337E, S244D / A335L / I337E, G241A, G241 A / S244D / I337E, G241A / A335L / I337E,G241A / S244D / A335L / I337E, F248L / R297P / Y305LA / 310I / P401 L, and L240V / F248L / R297P / Y305L / P401 L the amino acid residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3, or any other combination; or a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3. In yet other aspects of these embodiments, the one or more additional amino acid substitutions increases Fc-related effector function and is selected from S299A / E334A / K335A, S240D / I333E, S240D / A331 L / I333E, G237A, G237A / S240D / I333E, G237A / A331 L / I333E,G237A / S240D / A331 L / I333E, F244L / R293P / Y301 LA / 306I / P397L, and L236V / F244L / R293P / Y301 L / P397L the amino acid residue positions based on IgG heavy chainsequence SEQ ID NO: 4, or any other combination; or a combination of L235Y / L236Q / G237W / S240M / H269D / D271 E / S299A on one heavy chain and D271 E / K327D / A331 M / K335E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4.

[0086] An IgG antibody variant disclosed herein can be used in a wide array of treatment methods and uses. For example, an IgG antibody variant disclosed herein can be used in methods and uses for treating a disease in a pregnant woman, for preventing or attenuating increased disease activity in a pregnant woman, for treating a disease in a woman still breastfeeding an infant, for preventing or attenuating increased disease activity in a woman still breastfeeding an infant, for treating a disease in a non-pregnant woman of childbearing age, for preventing or attenuating increased disease activity in a non-pregnant woman of childbearing age, for reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant woman being treated a disease, for reducing likelihood and extent of unwanted effects on a on a breastfeeding baby being breastfed by a woman being treated a disease, for preventing or minimizing FcRn-dependent active transport of an IgG antibody from a pregnant woman across the placenta to her unborn baby, and / or for preventing or minimizing FcRn-dependent active transport of an IgG antibody from a breastfeeding woman to a breastfeeding infant.

[0087] The present specification discloses methods and uses of treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the disease is treatable with a composition comprising an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses a use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament for treating adisease in a pregnant subject in need thereof while minimizing unwanted side effects to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0088] The present specification discloses methods and uses of preventing or attenuating increased disease activity in a pregnant subject in need thereof due to an adverse pregnancy outcome to an unborn baby, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or attenuating increased disease activity due to adverse pregnancy outcome to an unborn baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0089] The present specification discloses methods and uses of treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses provides a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a breastfeeding subject in need thereofwhile minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament for treating a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on a breastfeeding baby, wherein the IgG antibody variant disclosed herein is directed to a therapeutic target forthe disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0090] The present specification discloses methods and uses of treating a disease in a nonpregnant subject of childbearing age in need thereof, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease, and wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception. In some embodiments, a method disclosed herein comprises administering to the non-pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target forthe disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibodyvariant disclosed herein from the non-pregnant subject to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for protection of an unborn baby from the time of a potential conception, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0091] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a neurodegenerative disease, disorder, or condition. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease Huntington’s disease, primary progressive multiple sclerosis; secondary progressive multiple sclerosis, corticobasal degeneration, Rett syndrome,; anterior ischemic optic neuropathy; glaucoma; uveitis; depression; trauma-associated stress or post-traumatic stress disorder, frontotemporal dementia, Lewy body dementias, mild cognitive impairments, posterior cortical atrophy, primary progressive aphasia, or progressive supranuclear palsy, or any combination thereof.

[0092] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a tauopathy. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia pugilistica, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden- Spatz disease, Huntington's disease, ganglioglioma, gangliocytoma, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Lytico-Bodig disease (Parkinson-dementia complex of Guam), meningioangiomatosis, Parkinsonism disease linked to chromosome 17, Pick’s disease, primary age-related tauopathy (PART), formerly known as neurofibrillary tangle-only dementia (NFT- dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis, or tuberous sclerosis, or any combination thereof.

[0093] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a retinal degeneration disorder. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes age-related macular degeneration (wet and dry), retinitis pigmentosa, choroideremia, cone-rod retinal dystrophy, gyrate atrophy, juvenile retinoschisis, vitelliform macular dystrophy (Best’sdisease), abetalipoproteinemia (Bassen-Kornzweig disease), Bardet-Biedl syndrome, blue cone monochromatism disease, dominant drusen, Goldman-Favre vitreoretinal dystrophy (enhanced s-cone syndrome), Kearns-Sayre syndrome, Laurence-Moon syndrome, Leber’s congenital amaurosis, Leber’s refsum disease, Oguchi disease, peripapillary (pericentral) choroidal dystrophy, pigment pattern dystrophy, Sorsby macular dystrophy, Stargardt’s disease, Stickler’s syndrome, Usher syndrome, or Wagner's vitreoretinal dystrophy, or any combination thereof.

[0094] The present specification discloses methods and uses of treating a disease in a nonpregnant subject of childbearing age in need thereof, wherein the disease is treatable with an IgG antibody directed to a therapeutic target for the disease, and wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby. In some embodiments, a method disclosed herein comprises administering to the non-pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non- pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in treating a disease in a non- pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein is directed to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the treatment is initiated prophylactically for preventing increased disease activity in the non-pregnant subject due to adverse outcome of potential pregnancy to an unborn baby, and wherein the IgG antibody variant disclosed herein isdirected to the therapeutic target for the disease, thereby if the non-pregnant subject becomes pregnant, the IgG antibody variant disclosed herein reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the non-pregnant subject to the unborn baby.

[0095] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a neurodegenerative disease, disorder, or condition. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease Huntington’s disease, primary progressive multiple sclerosis; secondary progressive multiple sclerosis, corticobasal degeneration, Rett syndrome,; anterior ischemic optic neuropathy; glaucoma; uveitis; depression; trauma-associated stress or post-traumatic stress disorder, frontotemporal dementia, Lewy body dementias, mild cognitive impairments, posterior cortical atrophy, primary progressive aphasia, or progressive supranuclear palsy, or any combination thereof.

[0096] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a tauopathy. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia pugilistica, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden- Spatz disease, Huntington's disease, ganglioglioma, gangliocytoma, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Lytico-Bodig disease (Parkinson-dementia complex of Guam), meningioangiomatosis, Parkinsonism disease linked to chromosome 17, Pick’s disease, primary age-related tauopathy (PART), formerly known as neurofibrillary tangle-only dementia (NFT- dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis, or tuberous sclerosis, or any combination thereof.

[0097] In some embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes a retinal degeneration disorder. In aspects of these embodiments, the disclosed disease treatable with an IgG antibody directed to a therapeutic target excludes age-related macular degeneration (wet and dry), retinitis pigmentosa, choroideremia, cone-rod retinal dystrophy, gyrate atrophy, juvenile retinoschisis, vitelliform macular dystrophy (Best’s disease), abetalipoproteinemia (Bassen-Kornzweig disease), Bardet-Biedl syndrome, blue cone monochromatism disease, dominant drusen, Goldman-Favre vitreoretinal dystrophy (enhanced s-cone syndrome), Kearns-Sayre syndrome, Laurence-Moon syndrome, Leber’s congenital amaurosis, Leber’s refsum disease, Oguchi disease, peripapillary (pericentral) choroidaldystrophy, pigment pattern dystrophy, Sorsby macular dystrophy, Stargardt’s disease, Stickler’s syndrome, Usher syndrome, or Wagner's vitreoretinal dystrophy, or any combination thereof.

[0098] The present specification discloses methods and uses of reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0099] The present specification discloses methods and uses of reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprisesadministering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to the therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in reducing likelihood and extent of unwanted effects on a breastfeeding baby fed by a breastfeeding subject in need thereof, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn- dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0100] The present specification discloses methods and uses of preventing or minimizing FcRn- dependent active transport of an IgG antibody from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is afflicted with a disease that is treatable with an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the pregnant subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use preventing or minimizing FcRn- dependent active transport of an IgG antibody from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variantdisclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in preventing or minimizing FcRn- dependent active transport of an IgG antibody directed to a therapeutic target from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject across the placenta to the unborn baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or minimizing FcRn-dependent active transport of an IgG antibody directed to a therapeutic target from a pregnant subject across the placenta to an unborn baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the pregnant subject to the unborn baby.

[0101] The present specification discloses methods and uses of preventing or minimizing FcRn- dependent active transport of an IgG antibody directed to a therapeutic target from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is afflicted with a disease that is treatable with an IgG antibody directed to a therapeutic target for the disease. In some embodiments, a method disclosed herein comprises administering to the breastfeeding subject a composition comprising an IgG antibody variant disclosed herein directed to a therapeutic target that reduces an FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses a composition comprising an IgG antibody variant disclosed herein for use preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of a composition comprising an IgG antibody variant disclosed herein in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the breastfeeding subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for thedisease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby. In some embodiments, present specification discloses use of an IgG antibody variant disclosed herein in the manufacture of a medicament in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant disclosed herein from a breastfeeding subject to a breastfeeding baby, wherein the pregnant subject is undergoing treatment of a disease using an IgG antibody directed to a therapeutic target for the disease, and wherein the IgG antibody variant disclosed herein is directed to a therapeutic target for the disease and reduces FcRn-dependent active transport of the IgG antibody variant disclosed herein from the breastfeeding subject to the breastfeeding baby.

[0102] An unborn baby refers to the in utero developmental stages of zygote, embryo, and fetus of a human being. A newborn infant and breast-feeding baby refer to an ex utero human individual covering the first 24 months of age. A pregnant subject refers to a woman who is pregnant with an unborn baby. A breastfeeding subject refers to a woman who is lactating and capable of breastfeeding newborn infant and breast-feeding baby. A non-pregnant subject of childbearing age refers to a pre-menopausal woman who is still capable of conceiving a baby.

[0103] The present specification discloses an unwanted side effect. As used herein, the term “unwanted side effect” refers to an adverse or undesirable event or effect caused or associated with a medication or medical treatment of treatment. Non-limiting examples of an unwanted side effect include a shorter than normal 40-week pregnancy term, such as, e.g., less than 38 weeks, less than 36 weeks, less than 34 weeks, less than 30 weeks, delayed or abnormal development of an unborn baby or newborn infant, miscarriage or death of an unborn baby or newborn infant, loss of weight in newborns, increase in premature diabetes, or impaired or motor or cognitive skills of the child, as compared with pregnancies in untreated women.

[0104] The term “unwanted exposure” as used herein refers to exposure of an unborn baby, newborn infant, or breastfeeding baby to a therapeutic antibody disclosed herein that leads to unwanted side effects.

[0105] The present specification discloses an IgG antibody directed to a therapeutic target for the disease. An IgG antibody directed to a therapeutic target for the disease is typically a therapeutic antibody. Both an IgG antibody variant disclosed herein as well as its corresponding reference antibody are considered a therapeutic antibody or “an IgG antibody directed to a therapeutic target for the disease” as used herein. A therapeutic antibody disclosed herein may be specific to an antigen that is a cell surface receptor and may be antagonistic if the purpose is to inhibit the receptoractivity / signaling; or may be agonistic if the purpose is to activate the receptor activity / signaling. It is also possible that a therapeutic antibody disclosed herein is a blocking or neutralizing antibody, which competes with a specific receptor ligand for binding to the receptor; and if a therapeutic antibody disclosed herein is a ligand of a certain receptor, the therapeutic antibody may similarly be a blocking or neutralizing antibody, which prevents binding of the ligand to the receptor; or if the ligand has an activity of its own, a therapeutic antibody disclosed herein may be an antagonistic antibody. In case the antigen is an enzyme, a therapeutic antibody disclosed herein may inhibit, block, neutralize or activate the enzyme. In case the enzyme is a multifunctional exoenzyme, such as CD38, a therapeutic antibody disclosed herein may be inhibitory, activating and / or blocking.

[0106] An I g G antibody variant disclosed herein as well as a therapeutic antibody disclosed herein can be an antibody to an immune checkpoint. Immune checkpoints are often comprised of receptor-ligand pairs, and some are exoenzymes, for example as detailed in Table 2. In some embodiments, an IgG antibody variant or therapeutic antibody disclosed herein is an antagonistic, neutralizing, and / or blocking antibody specific to an immune checkpoint receptor / target having an inhibitory function listed in Table 2.

[0107] In some embodiments, an IgG antibody variant or therapeutic antibody disclosed herein is an antagonistic, neutralizing, and / or blocking antibody specific for a ligand to an immune checkpoint receptor / target having an inhibitory function listed in Table 2.

[0108] In some embodiments, an IgG antibody variant or therapeutic antibody disclosed herein is an agonistic antibody specific for a stimulatory checkpoint receptor / target having a stimulatory function listed in Table 2.

[0109] In some embodiments, an IgG antibody variant or therapeutic antibody disclosed herein is an antagonistic, neutralizing, and / or blocking antibody specific for a ligand to a stimulatory checkpoint receptor / target having a stimulatory function listed in Table 2.

[0110] In some embodiments, an IgG antibody variant or therapeutic antibody disclosed herein is specific to an antigen that is overexpressed on tumor cells (for example immune checkpoint molecules listed in Table 2), and the IgG antibody variant or therapeutic antibody comprises lgG1 or lgG3 Fc domains mediating Fc-related effector function, and in certain embodiments comprises substitutions that increase Fc-related effector function (see above), to evoke an immune response against the tumor cells.Table 2. Immune Checkpoint Molecules

[0111] In certain embodiments, the disease being treated with the therapeutic antibody of any one of the above embodiments, including therapeutic antibodies specific to an immune checkpoint molecule listed in Table 2, is cancer.

[0112] In certain embodiments, the disease is cancer, and the therapeutic IgG antibody is specific to an antigen selected from the lists in Table 3 and Table 4.Table 3. FDA-Approved Monoclonal Antibodies for Cancer*

[0113] In certain embodiments, the antagonistic therapeutic anti-PD-L1 IgG antibody is an antibody as defined in WO 2020 / 215049.

[0114] In certain embodiments, the disease is an autoimmune disease, and the binding specificity of the therapeutic IgG antibody is to an antigen, selected from the lists in Table 5 and Table 6.Table 5. Cytokine-Targeted Therapies for Treatment of Autoimmune Diseases***

[0115] In some embodiments, the known, unaltered, or original human or humanized IgG antibody mentioned above is a human or humanized IgG antibody directed to a therapeutic target. Examples of human or humanized IgG antibodies directed to a therapeutic target are antibodies tested in clinical trials. Structural information regarding these antibodies can be found at clinicaltrials.org. In certain embodiments, wherein said human or humanized IgG antibody is directed to a therapeutic target selected from Table 7 or Table 8.

[0116] In certain embodiments, the human or humanized IgG antibody is selected from Table 7 or Table 8.

[0117] In certain embodiments, the human or humanized IgG antibody, it’s therapeutic target and the indication is as indicated in Table 7 or Table 8.

[0118] In certain embodiments, the therapeutic target is selected from CD96, CD226 (DNAM-1), CD112, CD155 (Dougall, et al., TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy Immunological Reviews 276: 112-120, 2017); CD200, CD200R (Mahadevan et al., Phase I Study of Samalizumab In Chronic Lymphocytic Leukemia and Multiple Myeloma: Blockade of the Immune Checkpoint CD200, J. Immunorher. Cancer 7: 227, 2019); Siglec-7, Siglec-9 (Ibarlucea-Benitez, Siglecs-7 / 9 Function as Inhibitory Immune Checkpoints in vivo and can be Targeted to Enhance Therapeutic Antitumor Immunity, PNAS 18(26): e2107424118, 2021); SIRPa, CD47 (Veillette et al., SIRPa-CD47 Immune Checkpoint Blockade in Anticancer Therapy, Trends Immunol. 39: 32018, 2018; PVRIG (Li et al., Blockade of Checkpoint Receptor PVRIG Unleashes Anti-Tumor Immunity of NK Cells in Murine and Human Solid Tumors, J. Hematol. Oncol. 14: 100, 2021 ; WO 2018 / 033798); IDLR2 (WO 2020 / 207961); 2B4 (CD244, SLAMF), ILT2 (LIR1), KIR-L, KLRG-1 , and NKG2A / CD94 (Archilla-Ortega et al., Blockade of Novel Immune Checkpoints and New Therapeutic Combinations to Boost Antitumor Immunity, J. Exp. Clin. Cancer Res. 41 : 62, 2022).

[0119] The term “treating” as used herein refers to reducing, regressing, or eliminating in an individual a clinical symptom attributed to a disease disclosed herein or delaying or preventing in an individual the onset of a clinical symptom of a disease disclosed herein. T reating includes both a therapeutic treatment after the onset of a disease disclosed herein or a prophylactic treatment of a disease disclosed herein before its onset.

[0120] Pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers orexcipients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0121] The following exemplification of carriers, modes of administration, dosage forms, etc., are listed as known possibilities from which the carriers, modes of administration, dosage forms, etc., may be selected for use with the present invention. Those of ordinary skill in the art will understand, however, that any given formulation and mode of administration selected should first be tested to determine that it achieves the desired results.

[0122] Methods of administration include, but are not limited to, parenteral, e.g., intravenous, intraperitoneal, intramuscular, subcutaneous, mucosal (e.g., oral, intranasal, buccal, vaginal, rectal, intraocular), intrathecal, topical, and intradermal routes. Administration can be systemic or local.

[0123] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the active agent is administered. The carriers in the pharmaceutical composition may comprise a binder, such as microcrystalline cellulose, polyvinylpyrrolidone (polyvidone or povidone), gum tragacanth, gelatin, starch, lactose, or lactose monohydrate; a disintegrating agent, such as alginic acid, maize starch and the like; a lubricant or surfactant, such as magnesium stearate, or sodium lauryl sulphate; and a glidant, such as colloidal silicon dioxide.

[0124] For oral administration, the pharmaceutical preparation may be in liquid form, for example, solutions, syrups, or suspensions, or may be presented as a drug product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well-known in the art.

[0125] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0126] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0127] The compositions may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0128] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen free water, before use.

[0129] The compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0130] For administration by inhalation, the compositions for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0131] The determination of the doses of the active ingredient to be used for human use is based on commonly used practices in the art and will be finally determined by physicians in clinical trials. An expected approximate equivalent dose for administration to a human can be calculated based on the in vivo experimental evidence disclosed herein below, using known formulas (e.g., Reagan- Show et al., Dose Translation from Animal to Human Studies Revisited, FASEB J. 22: 659-661 , 2007). According to this paradigm, the adult human equivalent dose (mg / kg body weight) equals a dose given to a mouse (mg / kg body weight) multiplied with 0.081 .

[0132] Aspects of the present specification can also be described by the following embodiments:1 . A method for treatment of a disease in a pregnant subject in need thereof while minimizing unwanted side effects, or for preventing or attenuating increased disease activity due toadverse pregnancy outcome, wherein said disease is treatable with a human or humanized IgG antibody directed to a therapeutic target, wherein said method comprises administering to said pregnant subject a variant version of a human or humanized IgG antibody directed to a therapeutic target, wherein the light and heavy chains of said variant have identical amino acid sequences to those of the human or humanized IgG antibody, except for one or more amino acid substitutions in its Fc region that reduces binding affinity of the variant human or humanized IgG antibody to a neonatal Fc receptor (FcRn) relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thereby reducing FcRn- dependent active transport of the variant version of the human or humanized IgG antibody from the subject to their unborn baby relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thus protecting the unborn baby from unwanted exposure to the variant human or humanized IgG antibody while effectively treating the disease or preventing increased disease activity due to adverse pregnancy outcome. A method for treatment of a disease in a breastfeeding subject in need thereof while minimizing unwanted effects on their breastfeeding baby, wherein said disease is treatable with a human or humanized IgG antibody directed to a therapeutic target, wherein said method comprises administering to said breastfeeding subject a variant version of a human or humanized IgG antibody directed to a therapeutic target, wherein the light and heavy chains of the variant version have identical amino acid sequences to those of the human or humanized IgG antibody, except for one or more amino acid substitutions in its Fc region that reduces binding affinity of the variant human or humanized IgG antibody to a neonatal Fc receptor (FcRn) relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thereby reducing FcRn-dependent active transport of the variant version of the human or humanized IgG antibody from the subject to their baby relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thus protecting the baby from unwanted exposure to the variant human or humanized IgG antibody while effectively treating the disease. A method for treatment of a disease in a non-pregnant subject of childbearing age in need thereof, wherein said disease, excluding Alzheimer’s disease, is treatable with a human or humanized IgG antibody directed to a therapeutic target, wherein said method comprises administering to said non-pregnant subject a variant version of a human or humanized IgG antibody directed to a therapeutic target, wherein the light and heavy chains of the variant version have identical amino acid sequences to those of the human or humanized IgG antibody, except for one or more amino acid substitutions in its Fc region that reduces binding affinity of the variant human or humanized IgG antibody to a neonatal Fc receptor (FcRn) relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thereby, if the subject becomes pregnant, reducing FcRn-dependent activetransport of the variant version of the human or humanized IgG antibody from the subject to the unborn baby relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thus protecting the unborn baby from unwanted exposure to the variant human or humanized IgG antibody while effectively treating the disease. A method for reducing likelihood and extent of unwanted effects on an unborn baby and / or minimizing likelihood of miscarriage in a pregnant subject in need thereof, or for reducing likelihood and extent of unwanted effects on a baby fed by a breastfeeding subject in need thereof, and the subject is undergoing treatment of a disease that is treatable with a human or humanized IgG antibody directed to a therapeutic target, wherein said method comprises administering to said subject a variant version of a human or humanized IgG antibody directed to a therapeutic target, wherein the light and heavy chains of the variant version have identical amino acid sequences to those of the human or humanized IgG antibody IgG antibody, except for one or more amino acid substitutions in its Fc region that reduces binding affinity of the human or humanized IgG antibody IgG antibody to a neonatal Fc receptor (FcRn) relative to the human or humanized IgG antibody lacking the one or more amino acid modifications, thereby reducing FcRn-dependent active transport of the variant version of the human or humanized IgG antibody from the subject to the unborn baby or baby relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications, thus reducing unwanted effects on an unborn baby, preventing or minimizing likelihood of miscarriage, and / or reducing likelihood and extent of unwanted effects on a baby fed by a breastfeeding subject, relative to the human or humanized IgG antibody that is lacking the one or more amino acid modifications. A method for preventing or minimizing FcRn-dependent active transport of a human or humanized IgG antibody directed to a therapeutic target from a pregnant subject to their unborn baby or from a breastfeeding subject to their baby, wherein said subject is afflicted with a disease that is treatable with a human or humanized IgG antibody directed to a therapeutic target, wherein the method comprises administering to said subject a variant version of a human or humanized IgG antibody directed to a therapeutic target, wherein the light and heavy chains of the variant version have identical amino acid sequences to those of the human or humanized IgG antibody, except for one or more amino acid substitutions in its Fc region that reduces binding affinity of the human or humanized IgG antibody to a neonatal Fc receptor (FcRn) relative to the IgG antibody that is lacking the one or more amino acid modifications, thereby reducing FcRn-dependent active transport of the variant version of the human or humanized IgG antibody across the placenta to the unborn baby relative to the human or humanized IgG antibody lacking the one or more amino acid modifications. The method of any one of embodiments 1 to 5, wherein said human or humanized IgG antibody is selected from lgG1 , lgG2, lgG3 and lgG4.. The method of any one of embodiments 1 to 6, wherein said one or more amino acid substitutions in the Fc region are at an amino acid residue position selected from 252-256 in the CH2 domains and positions 310, 433, 434, and 435 in the CH3 domains, or any combination thereof. . The method of claim 7, wherein said amino acid substitution is H310A, H435Q or a combination thereof. . The method of any one of embodiments 1 to 8, wherein said antibody comprises one or more additional amino acid substitutions in its Fc region that modify Fc-related effector function. 0. The method of claim 9, wherein said one or more additional amino acid substitutions reduces Fc-related effector function and is selected from L234A, L235A, K322A, or a combination thereof. 1 . The method of claim 9, wherein said one or more additional amino acid substitutions increasesFc-related effector function and is selected from S298A / E333A / K334A, S239D / I332E, S239D / A330L / I332E, G236A, G236A / S239D / I332E, G236A / A330L / I332E,G236A / S239D / A330L / I332E, F243L / R292P / Y300LA / 305I / P396L, andL235V / F243L / R292P / Y300L / P396L, or any other combination; or a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain andD270E / K326D / A330M / K334E on an opposing heavy chain. 2. The method of any one of embodiments 1 to 1 1 , wherein said disease is selected from cancer, autoimmune disease, sepsis, pulmonary fibrosis, inflammatory disease, viral or bacterial infection, and any one of the indications listed in the Tables below. 3. The method of any one of embodiments 1 to 12, wherein said human or humanized IgG antibody directed to a therapeutic target is a therapeutic human or humanized IgG antibody. 4. The method of embodiment 13, wherein said disease is cancer and the therapeutic IgG antibody is specific to an antigen selected from the lists in Table 3 and Table 4. 5. The method of embodiment 13, wherein said therapeutic antibody is selected from: a. an antagonistic / neutralizing / blocking antibody specific to an immune checkpoint receptor / target having an inhibitory function listed in Table 2; b. an antagonistic / neutralizing / blocking antibody specific for a ligand to an immune checkpoint receptor / target having an inhibitory function listed in Table 2; c. an agonistic antibody specific for a stimulatory checkpoint receptor / target having a stimulatory function listed in Table 2; d. an antagonistic / neutralizing / blocking antibody specific for a ligand to a stimulatory checkpoint receptor / target having a stimulatory function listed in Table 2; and e. a therapeutic antibody specific to an antigen that is overexpressed on tumor cells listed in Table 2, and the therapeutic antibody comprises IgG 1 or lgG3 Fc domains mediating Fc- related effector function.16. The method of embodiment 15, wherein said antagonistic / neutralizing / blocking therapeutic anti-PD-L1 IgG antibody is an antibody as defined in WO 2020 / 215049.17. The method of embodiment 15 or 16, wherein said disease is cancer.18. The method of embodiment 13, wherein the disease is an autoimmune disease, and the binding specificity of the therapeutic IgG antibody is to an antigen, selected from the lists in Table 5 and Table 6.19. The method of any one of embodiments 1 to 12, wherein said human or humanized IgG antibody is directed to a therapeutic target selected from Table 7 or Table 8.20. The method of embodiment 19, wherein the human or humanized IgG antibody is selected from Table 7 or Table 8.21. The method of embodiment 20, wherein the human or humanized IgG antibody, it’s therapeutic target and the indication is as indicated in Table 7 or Table 8.22. The method of any one of embodiments 1 to 12, wherein said human or humanized IgG antibody is directed to a therapeutic target selected from CD96, CD226 (DNAM-1), CD1 12, CD155; CD200, CD200R; Siglec-7, Siglec-9; SIRPa, CD47; PVRIG; IDLR2; 2B4, ILT2 (LIR1), KIR-L, KLRG-1 , NKG2A / CD94.

[0133] Aspects of the present specification can also be described by the following embodiments:1. A method of treating a disease in a pregnant subject in need thereof while minimizing one or more unwanted side effects to an unborn baby of the pregnant subject, the method comprising administering to the pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the unborn baby relative to the reference antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby, thereby protecting the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject.2. A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a pregnant subject in need thereof while minimizing one or more unwanted side effects to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to aneonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a pregnant subject in need thereof while minimizing one or more unwanted side effects to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for treating a disease in a pregnant subject in need thereof while minimizing one or more unwanted side effects to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A method of preventing or attenuating increased disease activity in a pregnant subject in need thereof due to an adverse pregnancy outcome to an unborn baby of the pregnant subject, the method comprising administering to the pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to an unborn baby relative to the reference antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby, thereby protecting the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject. A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or attenuating increased disease activity of a pregnant subject due to an adverse pregnancy outcome to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or moreamino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or attenuating increased disease activity of a pregnant subject due to an adverse pregnancy outcome to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for preventing or attenuating increased disease activity of a pregnant subject due to an adverse pregnancy outcome to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A method of treating a disease in a breastfeeding subject in need thereof while minimizing one or more unwanted side effects to a breastfeeding baby of the breastfeeding subject, the method comprising administering to the breastfeeding subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the breastfeeding baby relative to the reference antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the breastfeeding subject to the breastfeeding baby, thereby protecting the breastfeeding baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the breastfeeding subject. A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a breastfeeding subject in need thereof while minimizing one or more unwanted side effects to a breastfeeding baby of the breastfeedingsubject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. 1 . A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a breastfeeding subject in need thereof while minimizing one or more unwanted side effects to a breastfeeding baby of the breastfeeding subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. 2. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for treating a disease in a breastfeeding subject in need thereof while minimizing one or more unwanted side effects to a breastfeeding baby of the breastfeeding subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. 3. A method of treating a disease in a non-pregnant subject of childbearing age in need thereof, the method comprising administering to the non-pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the breastfeeding baby relative to the reference antibody, wherein the non-pregnant subject of childbearing age is subject to a potential pregnancy of an unborn baby; and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject, thereby if the non-pregnant subject becomes pregnant, the method prophylactically protects the unborn baby at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject.A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for treating a disease in a non-pregnant subject of childbearing age in need thereof, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A method of preventing increased disease activity in a non-pregnant subject of childbearing age, the method comprising administering to the non-pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acidsubstitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the breastfeeding baby relative to the reference antibody, wherein the non-pregnant subject of childbearing age is subject to a potential pregnancy of an unborn baby; and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject, thereby if the non-pregnant subject becomes pregnant, the method prophylactically protects the unborn baby at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing increased disease activity in a non-pregnant subject of childbearing age, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non- pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing increased disease activity in a non-pregnant subject of childbearing age, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for preventing increased disease activity in a non-pregnant subject of childbearing age, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgGantibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant and wherein the FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject is reduced, thereby if the non-pregnant subject becomes pregnant, an unborn baby is prophylactically protected at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject. A method of preventing or minimizing FcRn-dependent active transport of a therapeutic antibody from a pregnant subject to an unborn baby of the pregnant subject, the method comprising administering to the pregnant subject a composition comprising an IgG antibody variant of the therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the unborn baby relative to the reference antibody, wherein the pregnant subject is afflicted with a disease that is treatable with the IgG antibody variant of the therapeutic antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby, thereby protecting the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject. A composition comprising a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a pregnant subject to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a pregnant subject to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the referenceantibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a pregnant subject to an unborn baby of the pregnant subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A method of preventing or minimizing FcRn-dependent active transport of a therapeutic antibody from a breastfeeding subject to a breastfeeding baby of the breastfeeding subject, the method comprising administering to the breastfeeding subject a composition comprising an IgG antibody variant of the therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the breastfeeding baby relative to the reference antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the breastfeeding subject to the breastfeeding baby, thereby protecting the breastfeeding baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the breastfeeding subject. A composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a breastfeeding subject to a breastfeeding baby of the breastfeeding subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of a composition comprising an IgG antibody variant of a therapeutic antibody for use in preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a breastfeeding subject to a breastfeeding baby of the breastfeeding subject t, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of theIgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. A use of an IgG antibody variant of a therapeutic antibody in the manufacture of a medicament for preventing or minimizing FcRn-dependent active transport of the IgG antibody variant of the therapeutic antibody from a breastfeeding subject to a breastfeeding baby of the breastfeeding subject, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-28, wherein the IgG antibody variant is a human IgG antibody or a humanized IgG antibody. The methods, compositions, and uses of any one of embodiments 1-29, wherein the IgG antibody variant of the therapeutic antibody is lgG1 , lgG2, lgG3, or lgG4. The methods, compositions, and uses of any one of embodiments 1-30, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L234, L235, G236, S239, F243, K248, T250, M252, I253, S254, R255, T256, P257, H268,D270, E272, H285, K288, K290, P291 , R292, S298, Y300, V305, V308, L309, H310, Q311 ,L314, K322, K326, A330, I332, E333, K334, D356, E357, L358, P396, S415, M428, H433,N434, H435, or Y436, or any combination thereof, the amino acid residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L235, L236, G237, S240, F244, K249, T251 , M253, I254, S255, R256, T257, P258, H269, D271 , E273, H286, K289, K291 , P292, R293, S299, Y301 , V306, V309, L310, H31 1 , Q312, L315, K323, K327, A331 , I333, E334, K335, D357, E358, L359, P397, S416, M429, H434, N435, H436, or Y437, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4. The methods, compositions, and uses of any one of embodiments 1-31 , wherein the one or more amino acid substitutions are located in the Fc region further include one or more amino acid substitutions located at amino acid residue positions L234, L235, I253, T256, K288,H310, K322, S415, H433, H435, or Y436, or any combination thereof, the amino acid residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1 ; or wherein the one or more amino acid substitutions are located in the Fc region further include one or more amino acid substitutions located at amino acid residue positions L239, L240, I258. T261 , K293, H315, K327, S420, H438, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions are located in the Fc region further include one or more amino acid substitutions located at amino acid residue positions L235, L236, I254, T257, K289, H311 , K323, S416, H434, H436, or Y437, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4. The methods, compositions, and uses of any one of embodiments 1-32, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions 234, L235, H310, K322, or H435, or any combination thereof, the amino acid residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, or H440, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L235, L236, H31 1 , K323, or H436, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4. The methods, compositions, and uses of any one of embodiments 1-33, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions 234, L235, H310, K322, and H435, the amino acid residue positions based on the EU numbering system generalized for all antibodies as shown in Table 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, and H440, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L235, L236, H311 , K323, and H436, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4. The methods, compositions, and uses of any one of embodiments 1-34, wherein the one or more amino acid substitutions located in the Fc region further includes S298A / E333A / K334A, S239D / I332E, S239D / A330L / I332E, G236A, G236A / S239D / I332E, G236A / A330L / I332E, G236A / S239D / A330L / I332E, F243L / R292P / Y300L / V305I / P396L, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region further include a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positionsbased on the EU numbering system generalized for all antibodies as shown in Table 1 ; or further includes S303A / E338A / K339A, S244D / I337E, S244D / A335L / I337E, G241A,G241 A / S244D / I337E, G241 A / A335L / I337E, G241A / S244D / A335L / I337E,F248L / R297P / Y305LA / 310I / P401 L, and L240V / F248L / R297P / Y305L / P401 L the amino acid residue positions based on IgG heavy chain sequences SEQ ID NO: 1 , or any other combination; or a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequences SEQ ID NO: 1 ; or further includes S299A / E334A / K335A, S240D / I333E, S240D / A331 L / I333E, G237A, G237A / S240D / I333E,G237A / A331 L / I333E, G237A / S240D / A331 L / I333E, F244L / R293P / Y301 L / V306I / P397L, and L236V / F244L / R293P / Y301 L / P397L the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4, or any other combination; or a combination of L235Y / L236Q / G237W / S240M / H269D / D271 E / S299A on one heavy chain and D271 E / K327D / A331 M / K335E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 4 The methods, compositions, and uses of any one of embodiments 1-35, wherein the therapeutic antibody is an anti-2B4 antibody, an anti- a4p7 integrin antibody, an anti-AXL antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H7 antibody, an anti-B7RP1 antibody, an anti-BAFF antibody, an anti-BAFFR antibody, an anti-BLyS antibody, anti-BTLA antibody, an anti-CCN2 antibody, an anti-CCR4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-C5 antibody, an anti-C19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD38 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti- CD40L antibody, an anti-CD47 antibody, an anti-CD52 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD79p antibody, an anti-CD80 antibody, an anti-CD86 antibody, an anti-CD93 antibody, an anti-CD94 antibody, an anti-CD96 antibody, an anti-CD112 antibody, an anti-CD137 antibody, an anti-CD137L antibody, an anti-CD155 antibody, an anti- CD160 antibody, an anti-CD161 antibody, an anti-CD200 antibody, an anti-CD200R antibody, an anti-CD226 antibody, an anti-CGRP antibody, an anti-CGRPR antibody, an anti-CTLA-4 antibody, an anti-Dabigatran antibody, an anti-DNAM-1 antibody, an anti-EGFR antibody, an anti-EphA3R antibody, an anti-Factor IXa-X antibody, an anti-FGF23 antibody, an anti-FKN antibody, an anti-Galectin-9 antibody, an anti-GD2 antibody, an anti-GITR antibody, an antienterotoxin B (Clostridium difficile) antibody, an anti-GM-CSF antibody, an anti-GPIIb / llla antibody, an anti-HER2 antibody, an anti-HVEM antibody, an anti-ICOS antibody, an anti- ICOSL antibody, an anti-IDLR2 antibody, an anti-lgE antibody, an anti-IL-1 p antibody, an anti- IL-4Ra antibody, an anti-IL-5 antibody, an anti-IL-5Ra antibody, an anti-IL-6 antibody, an anti- IL-6R antibody, an anti-IL-8 antibody, an anti-IL-13 antibody, an anti-IL-17a antibody, an anti-IL-17R antibody, an anti-IL-12 / 23 antibody, an anti-IL-23p19 antibody, an anti-ILT2 antibody, an anti-IFN-aR1 antibody, an anti-IFNy antibody, an anti-ITGA4 antibody, an anti-KIR antibody, an anti-KIR-L antibody, an anti-KIR2DL1 antibody, an anti-KIR2DL2 antibody, an anti-KIR2DL3 antibody, an anti-KIR3DL2 antibody, an anti-KLRG-1 antibody, an anti-LAG-3 antibody, an anti- LFA1 antibody, an anti-LIF antibody, an anti-LIR1 antibody, an anti-MAG antibody, an anti- MHC Class I molecule antibody, an anti-MHC Class II molecule antibody, an anti-NKG2A antibody, an anti-OX40 antibody, an anti-OX40L antibody, an anti-P-Selectin antibody, an anti- PA (8. anthrasis) antibody, an anti-PCSK9 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-PDGFRa antibody, an anti-Plasma Kallikrein antibody, an anti-PVRIG antibody, an anti-RANKL antibody, an anti-RSV antibody, an anti- Sclerostin antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec-15 antibody, an anti-SIRPa antibody, an anti-SLAMF7 antibody, an anti-TIGIT antibody, an anti- TIM-3 antibody, an anti-TNFa antibody, an anti-TSLP antibody, an anti-VEGF antibody, an anti-VEGF-A antibody, an anti-VEGFR2 antibody, an anti-VISTA antibody, or an anti-von Willebrand factor antibody. The methods, compositions, and uses of any one of embodiments 1-36, wherein the disease is an acute ischemic stroke, an asthma, an autoimmune disease, sepsis, a bacterial infection, a cancer, a diabetic nephropathy, an inflammatory disease, a psoriasis, a pulmonary fibrosis, a rheumatoid arthritis, a systemic lupus erythematosus, or a viral infection. The methods, compositions, and uses of any one of embodiments 1-37, wherein the IgG antibody variant has a low association rate constant for FcRn. The methods, compositions, and uses of any one of embodiments 1-38, wherein the IgG antibody variant has an association rate constant for FcRn of, e.g., less than 1 x 10° M1s1, less than 1 x 101M1S'1, less than 1 x 102M1S'1, less than 1 x 103M1S'1, less than 1 x 104M’1S'1, or less than 1 x 105M1S'1; and / or an association rate constant for FcRn of, e.g., more than 1 x 10° M1s1, more than 1 x 101M1s1, more than 1 x 102M1s1, more than 1 x 103M-1S'1, more than 1 x 104M1s1, or more than 1 x 105M1s1; an association rate constant for FcRn of between 1 x 10° M1s1to 1 x 101M1s1, 1 x 10° M1s1to 1 x 102M1s1, 1 x 10° M1S'1to 1 x 103M'1S'1, 1 x 10° M'1S'1to 1 x 104M'1s1, 1 x 10° M'1s1to 1 x 105M'1s1, 1 x 101M'1S'1to 1 x 102M'1S'1, 1 x 101M'1S'1to 1 x 103M'1s1, 1 x 101M'1s1to 1 x 104M'1s1, 1 x101M'1S'1to 1 x 105M'1S'1, 1 x 102M'2s1to 1 x 103M'1s1, 1 x 102M'1s1to 1 x 104M'1s1,1 x 102M'1S'1to 1 x 105M'1S'1, 1 x 103M'1s1to 1 x 104M'1s1, 1 x 103M'1s1to 1 x 105M'1S'1, or 1 x 104M'1S'1to 1 x 105M1s1. The methods, compositions, and uses of any one of embodiments 1-39, wherein the IgG antibody variant has a low association rate constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.The methods, compositions, and uses of any one of embodiments 1-40, wherein the IgG antibody variant has an association rate constant for FcRn of, e.g., at least 1 x 101-fold less, at least 1 x 102-fo Id less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105- fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant; or an association rate constant for FcRn that is between, e.g., 1 x101to 1 x 102-fold less, 1 x 101to 1 x 103-fold less, 1 x 101to 1 x 104-fold less, 1 x 101to 1 x 105-fold less, 1 x 101to 1 x 106-fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 10®-fold less, 1 x 102to 1 x 103-fold less, 1 x 102to 1 x 104-fold less, 1 x 102to 1 x 105-fold less, 1 x102to 1 x 106-fold less, 1 x 102to 1 x 107-fold less, 1 x 102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x 106-fold less, 1 x 103to 1 x 107-fold less, 1 x 103to 1 x 108-fold less, 1 x 104to 1 x 105-fold less, 1 x 104to 1 x 106-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107-fold less, 1 x 105to 1 x 108-fold less, 1 x 106to 1 x 107-fold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-41 , wherein the IgG antibody variant has a high dissociation rate constant for FcRn. The methods, compositions, and uses of any one of embodiments 1-42, wherein the IgG antibody variant has a dissociation rate constant for FcRn of, e.g., less than 1 x 105s4, less than 1 x 106s4, less than 1 x 107s4, less than 1 x 10 ® s4, less than 1 x 10ss4, less than 1 x 1040s4, or less than 1 x 1041s4; and / or a dissociation rate constant for FcRn of, e.g., more than 1 x 10-5s4, more than 1 x 106s4, more than 1 x 10’7s4, more than 1 x 10 ® s4, more than 1 x 109s4, more than 1 x 1040s4, or more than 1 x 1041s4; or a dissociation rate constant for FcRn of between, e.g., 1 x 105s4to 1 x 106s4, 1 x 105s4to 1 x 107s4, 1 x 10-5s1to 1 x 10 ® s1, 1 x 105s1to 1 x 109s1, 1 x 105s1to 1 x 104° s1, 1 x 105s1to 1 x 1041s4, 1 x 10 ® s4to 1 x 10'7s4, 1 x 106s4to 1 x 10 ® s4, 1 x 10 ® s4to 1 x 109s4, 1 x 10’6s4to 1 x 1040s4, 1 x 10'6s4to 1 x 1041s4, 1 x 107s4to 1 x 10 ® s4, 1 x 107s4to 1 x 109s4, 1 x 10-7s4to 1 x 104° s4, 1 x 10-7s4to 1 x 1041s4, 1 x 10 ® s4to 1 x 109s4, 1 x 10 ® s4to 1 x 1040s4, 1 x 10 ® s4to 1 x 1041S’1, 1 x 10’9s4to 1 x 1040s4, 1 x 109s4to 1 x 1041s4, or 1 x 104° s4to 1 x 1041s4. The methods, compositions, and uses of any one of embodiments 1-43, wherein the IgG antibody variant has a higher dissociation rate constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant.The methods, compositions, and uses of any one of embodiments 1-44, wherein the IgG antibody variant has a dissociation rate constant for FcRn that is, e.g., at least 1 x 101-fold more, at least 1 x 102-fold more, at least 1 x 103-fold more, at least 1 x 104-fold more, at least 1 x 105-fold more, at least 1 x 10s-fold more, at least 1 x 107-fold more, or at least 1 x 108-fold more, than the dissociation rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant; or a dissociation rate constant for FcRn that is between, e.g., 1 x 101to 1 x 102-fold more, 1 x 101to 1 x 103-fold more, 1 x 101to 1 x 104-fold more, 1 x 101to 1 x 105-fold more, 1 x 101to 1 x 106-fold more, 1 x 101to 1 x 107-fold more, 1 x 101to 1 x 108- fold more, 1 x 102to 1 x 103-fold more, 1 x 102to 1 x 104-fold more, 1 x 102to 1 x 105-fold more, 1 x 102to 1 x 10®-fold more, 1 x 102to 1 x 107-fold more, 1 x 102to 1 x 108-fold more, 1 x 103to 1 x 104-fold more, 1 x 103to 1 x 105-fold more, 1 x 103to 1 x 106-fold more, 1 x 103to 1 x 107-fold more, 1 x 103to 1 x 108-fold more, 1 x 104to 1 x 105-fold more, 1 x 104to 1 x 106-fold more, 1 x 104to 1 x 107-fold more, 1 x 104to 1 x 108-fold more, 1 x 105to 1 x 106-fold more, 1 x 105to 1 x 107-fold more, 1 x 105to 1 x 108-fold more, 1 x 10® to 1 x 107-fold more, 1 x 106to 1 x 108-fold more, 1 x 107to 1 x 108-fold more, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-45, wherein the IgG antibody variant has a low equilibrium dissociation constant for FcRn. The methods, compositions, and uses of any one of embodiments 1-46, wherein the IgG antibody variant has an equilibrium dissociation constant for FcRn of, e.g., less than 1 pM, less than 10 pM, less than 0100 pM, less than 1 mM, less than 10 mM, or less than 100 mM; and / or an equilibrium dissociation constant for FcRn of, e.g., more than 1 pM, more than 10 pM, more than 0100 pM, more than 1 mM, more than 10 mM, or more than 100 mM; or an equilibrium dissociation constant for FcRn of between, e.g., 1 pM to 10 pM, 1 pM to 100 pM, 1 pM to 1 mM, 1 pM to 10 mM, 1 pM to 100 mM, 10 pM to 100 pM, 10 pM to 1 mM, 10 pM to 10 mM, 10 pM to 100 mM, 100 pM to 1 mM, 100 pM to 10 mM, 100 pM to 100 mM, 1 mM to 10 mM, 1 mM to 100 mM, or 10 mM to 100 mM. The methods, compositions, and uses of any one of embodiments 1-47, wherein the IgG antibody variant has a lower equilibrium dissociation constant for FcRn relative to an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-48, wherein the IgG antibody variant has an equilibrium dissociation constant for FcRn that is, e.g., at least 1 x 101-fold less, at least 1 x 102-fold less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105-fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant; or an equilibrium dissociation constant for FcRn that is between, e.g., 1 x 101to 1 x 102-fold less, 1 x 101to 1 x 103-fold less, 1 x 101to 1 x 104-fold less, 1 x 101to 1 x 105-fold less, 1 x 101to 1 x 106-fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 108-fold less, 1 x 102to 1 x 103-fold less, 1 x 102to 1 x 104-fold less, 1 x 102to 1 x105-fold less, 1 x 102to 1 x 106-fold less, 1 x 102to 1 x 107-fold less, 1 x 102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x 106-fold less, 1 x 103to 1 x 107-fold less, 1 x 103to 1 x 108-fold less, 1 x 104to 1 x 105-fold less, 1 x 104to 1 x106-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107-fold less, 1 x 105to 1 x 108-fold less, 1 x 106to 1 x 107-fold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 108-fold less, than the association rate constant of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-49, wherein the IgG antibody variant has a reduced binding affinity for FcRn that is, e.g., at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, or at least 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant; or a reduced binding affinity for FcRn that is, e.g., at most 10% less, at most 20% less, at most 30% less, at most 40% less, at most 50% less, at most 60% less, at most 70% less, at most 80% less, at most 90% less, or at most 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is between, e.g., about 10% to about 20% less, about 10% to about 30% less, about 10% to about 40% less, about 10% to about 50% less, about 10% to about 60% less, about 10% to about 70% less, about 10% to about 80% less, about 10% to about 90% less, about 10% to about 100% less, about 20% to about 30% less, about 20% to about 40% less, about 20% to about 50% less, about 20% to about 60% less, about 20% to about 70% less, about 20% to about 80% less, about 20% to about 90% less, about 20% to about 100% less, about 30% to about 40% less, about 30% to about 50% less, about 30% to about 60% less, about 30% to about 70% less, about 30% to about 80% less, about 30% to about 90% less, about 30% to about 100% less, about 40% to about 50% less, about 40% to about 60% less, about 40% to about 70% less, about 40% to about 80% less, about 40% to about 90% less, about 40% toabout 100% less, about 50% to about 60% less, about 50% to about 70% less, about 50% to about 80% less, about 50% to about 90% less, about 50% to about 100% less, about 60% to about 70% less, about 60% to about 80% less, about 60% to about 90% less, about 60% to about 100% less, about 70% to about 80% less, about 70% to about 90% less, about 70% to about 100% less, about 80% to about 90% less, about 80% to about 100% less, or about 90% to about 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-49, wherein the IgG antibody variant has a reduced binding affinity for FcRn that is, e.g., at least 1 x 101-fold less, at least 1 x 102-fold less, at least 1 x 103-fold less, at least 1 x 104-fold less, at least 1 x 105- fold less, at least 1 x 106-fold less, at least 1 x 107-fold less, or at least 1 x 108-fold less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant; or a reduced binding affinity for FcRn that is, e.g., at most 10% less, at most 20% less, at most 30% less, at most 40% less, at most 50% less, at most 60% less, at most 70% less, at most 80% less, at most 90% less, or at most 100% less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. In yet other aspects of these embodiments, an IgG antibody variant disclosed herein, like a human IgG antibody variant or a humanized IgG antibody variant, has a reduced binding affinity for FcRn that is between, e.g., 1 x 101to 1 x 102-fold less, 1 x 101to 1 x 103-fold less, 1 x 101to 1 x 104-fold less, 1 x 101to 1 x 105-fold less, 1 x 101to 1 x 106-fold less, 1 x 101to 1 x 107-fold less, 1 x 101to 1 x 108-fold less, 1 x 102to 1 x 103-fold less, 1 x 102to 1 x 104-fold less, 1 x 102to 1 x 105-fold less, 1 x 102to 1 x 106-fold less, 1 x 102to 1 x 107-fold less, 1 x102to 1 x 108-fold less, 1 x 103to 1 x 104-fold less, 1 x 103to 1 x 105-fold less, 1 x 103to 1 x106-fold less, 1 x 103to 1 x 107-fold less, 1 x 103to 1 x 108-fold less, 1 x 104to 1 x 105-fold less, 1 x 104to 1 x 10s-fold less, 1 x 104to 1 x 107-fold less, 1 x 104to 1 x 108-fold less, 1 x 105to 1 x 106-fold less, 1 x 105to 1 x 107-fold less, 1 x 105to 1 x 108-fold less, 1 x 106to 1 x107-fold less, 1 x 106to 1 x 108-fold less, 1 x 107to 1 x 108-fold less, than the binding affinity for FcRn of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-50, wherein the IgG antibody variant has a reduced FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby that is, e.g., 0% or less than 0.1 %, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1 %, less than 1.1%, less than 1.2%, less than 1.3%, lessthan 1.4%, less than 1.5%, less than 1.6%, less than 1.7%, less than 1.8%, less than 1.9%, less than 2%, less than 2.1 %, less than 2.2%, less than 2.3%, less than 2.4%, less than 2.5%, less than 2.6%, less than 2.7%, less than 2.8%, less than 2.9%, less than 3%, less than 3.1%, less than 3.2%, less than 3.3%, less than 3.4%, less than 3.5%, less than 3.6%, less than 3.7%, less than 3.8%, less than 3.9%, less than 4%, less than 4.1 %, less than 4.2%, less than 4.3%, less than 4.4%, less than 4.5%, less than 4.6%, less than 4.7%, less than 4.8%, less than 4.9%, less than 5%, less than 5.1 %, less than 5.2%, less than 5.3%, less than 5.4%, less than 5.5%, less than 5.6%, less than 5.7%, less than 5.8%, less than 5.9%, less than 6%, less than 6.1 %, less than 6.2%, less than 6.3%, less than 6.4%, less than 6.5%, less than 6.6%, less than 6.7%, less than 6.8%, less than 6.9%, less than 7%, less than 7.1 %, less than 7.2%, less than 7.3%, less than 7.4%, less than 7.5%, less than 7.6%, less than 7.7%, less than 7.8%, less than 7.9%, less than 8%, less than 8.1 %, less than 8.2%, less than 8.3%, less than 8.4%, less than 8.5%, less than 8.6%, less than 8.7%, less than 8.8%, less than 8.9%, less than 9%, less than 9.1 %, less than 9.2%, less than 9.3%, less than 9.4%, less than 9.5%, less than 9.6%, less than 9.7%, less than 9.8%, less than 9.9%, or less than 10% of the FcRn- dependent transport of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-50, wherein the IgG antibody variant has a reduced FcRn-dependent active transport of the IgG antibody variant from the breastfeeding subject to the breastfeeding baby that is, e.g., 0% or less than 0.1%, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1 %, less than 1.1 %, less than 1.2%, less than 1.3%, less than 1.4%, less than 1.5%, less than 1.6%, less than 1.7%, less than 1.8%, less than 1.9%, less than 2%, less than 2.1 %, less than 2.2%, less than 2.3%, less than 2.4%, less than 2.5%, less than 2.6%, less than 2.7%, less than 2.8%, less than 2.9%, less than 3%, less than 3.1 %, less than 3.2%, less than 3.3%, less than 3.4%, less than 3.5%, less than 3.6%, less than 3.7%, less than 3.8%, less than 3.9%, less than 4%, less than 4.1 %, less than 4.2%, less than 4.3%, less than 4.4%, less than 4.5%, less than 4.6%, less than 4.7%, less than 4.8%, less than 4.9%, less than 5%, less than 5.1 %, less than 5.2%, less than 5.3%, less than 5.4%, less than 5.5%, less than 5.6%, less than 5.7%, less than 5.8%, less than 5.9%, less than 6%, less than 6.1 %, less than 6.2%, less than 6.3%, less than 6.4%, less than 6.5%, less than 6.6%, less than 6.7%, less than 6.8%, less than 6.9%, less than 7%, less than 7.1 %, less than 7.2%, less than 7.3%, less than 7.4%, less than 7.5%, less than 7.6%, less than 7.7%, less than 7.8%, less than 7.9%, less than 8%, less than 8.1 %, less than 8.2%, less than 8.3%, less than 8.4%, less than 8.5%, less than 8.6%, less than 8.7%, less than 8.8%, less than 8.9%, less than 9%, less than 9.1 %, less than 9.2%, less than 9.3%, less than 9.4%, less than9.5%, less than 9.6%, less than 9.7%, less than 9.8%, less than 9.9%, or less than 10% of the FcRn-dependent transport of an IgG antibody that lacks the one or more amino acid modifications of the IgG antibody variant but otherwise has the same amino acid sequence as the IgG antibody variant. The methods, compositions, and uses of any one of embodiments 1-53, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes a neurodegenerative disease, disorder, or condition. The methods, compositions, and uses of any one of embodiments 1-54, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease Huntington’s disease, primary progressive multiple sclerosis; secondary progressive multiple sclerosis, corticobasal degeneration, Rett syndrome,; anterior ischemic optic neuropathy; glaucoma; uveitis; depression; trauma- associated stress or post-traumatic stress disorder, frontotemporal dementia, Lewy body dementias, mild cognitive impairments, posterior cortical atrophy, primary progressive aphasia, or progressive supranuclear palsy, or any combination thereof. The methods, compositions, and uses of any one of embodiments 1-53, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes a tauopathy. The methods, compositions, and uses of any one of embodiments 1-53 or 56, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes Alzheimer’s disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia pugilistica, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden-Spatz disease, Huntington's disease, ganglioglioma, gangliocytoma, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Lytico-Bodig disease (Parkinson-dementia complex of Guam), meningioangiomatosis, Parkinsonism disease linked to chromosome 17, Pick’s disease, primary age-related tauopathy (PART), formerly known as neurofibrillary tangle-only dementia (NFT-dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis, or tuberous sclerosis, or any combination thereof. The methods, compositions, and uses of any one of embodiments 1-53, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes a retinal degeneration disorder. The methods, compositions, and uses of any one of embodiments 1-53 or 58, wherein the disease treatable with an IgG antibody directed to a therapeutic target excludes age-related macular degeneration (wet and dry), retinitis pigmentosa, choroideremia, cone-rod retinal dystrophy, gyrate atrophy, juvenile retinoschisis, vitelliform macular dystrophy (Best’s disease), abetalipoproteinemia (Bassen-Kornzweig disease), Bardet-Biedl syndrome, blue cone monochromatism disease, dominant drusen, Goldman-Favre vitreoretinal dystrophy(enhanced s-cone syndrome), Kearns-Sayre syndrome, Laurence-Moon syndrome, Leber’s congenital amaurosis, Leber’s refsum disease, Oguchi disease, peripapillary (pericentral) choroidal dystrophy, pigment pattern dystrophy, Sorsby macular dystrophy, Stargardt’s disease, Stickler’s syndrome, Usher syndrome, or Wagner's vitreoretinal dystrophy, or any combination thereof.EXAMPLES

[0134] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.Example 1IgG with a H310A Substitution in Fc Region Reduces Placental Penetration

[0135] In this study, surr_null-H310A anti-PD-L1 antibody was tested for its ability for active transfer though the placenta from dam to embryo. The antibody surr_null-H310A anti-PD-L1 comprises a heavy chain of SEQ ID NO: 7 and a light chain of SEQ ID NO: 8 and comprises an Fc region hlgG 1 backbone having 3-point mutations (L235A, L236A, K323A) designed to reduce Fc effector function, and the H311A point mutation to enable enhanced clearance of the antibody from the circulation. This anti-PD-L1 antibody was derived from Variant 2-G09 which comprises a heavy chain of SEQ ID NO: 5 and a light chain of SEQ ID NO: 6. Specifically, the heavy chain of Variant 2-G09 was first modified by replacing the binding region with a binding region that binds murine PD-L1 to produce the heavy chain of SEQ ID NO: 7 of surr_null-H310A anti-PD-L1. As such, the surr_null-H310A anti-PD-L1 antibody, which contained the same modified hlgG1 backbone a Variant 2-G09, served as a surrogate antibody for Variant 2-G09 for mouse studies (see Table 9). The antibody surr_null anti-PD-L1 antibody, comprising a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10 and comprises the variable region of atezolizumab and a Fc region h IgG 1 backbone having 3-point mutations (L235A, L236A, K323A) designed to reduce Fc effector function. The antibody su rr_n ul I anti-PD-L1 antibody served as a control antibody and was identical to surr_null-H310A anti-PD-L1 except that the heavy chain of the surr_null anti-PD- L1 antibody lacked the H310A single point mutation.Table 9. Antibodies

[0136] A total of eight (8) female C57BL6 / J mice, about 10 weeks old, were inbred and maintained at an animal facility until the end of the study. In one series of experiments, dams were equally divided into two groups of four animals each. Each dam was administered with corresponding anti-PD-L1 antibody on day 17 of pregnancy. Group 1 animals (dams 1 , 5, 7, and 8) were each administered by intravenous injection a composition comprising 1.5mg of surr_null anti-PD-L1 antibody as single 200 pL bolus while Group 2 animals (dams 2, 3, 4, and 5) were each administered by intravenous injection a composition comprising 1.5 mg of surr_null-H310A anti- PD-L1 antibody as single 200 pL bolus (Table 10).

[0137] Dams were terminally anesthetized 24 hours post injection and whole blood from each dam was collected retro-orbitally into clot-activating tubes (MiniCollect; Greiner #450533) for serum isolation according to the manufacturer’s specifications. Up to 6 embryos were dissected from each dam, washed in PBS, and trunk blood was collected from each individual embryo and transferred into separate 0.5 mL Eppendorf tubes. Embryonic blood was allowed to clot for 30 minutes, then centrifuged for 5 minutes at 10,000 g. Serum samples were aliquoted and storedat -80°C. Embryonic blood from dam 1 of Group 1 animals and dam 2 of Group 2 animals was processed before complete clotting, resulting in hemolysis.

[0138] To evaluate anti-PD-L1 antibody concentration in the serum, reverse-sandwich enzyme- linked immunosorbent assays (rELISA) were conducted on each sample collected for each dam and embryo. Nunc MaxiSorpTM flat-bottom 96-well ELISA plates (Thermo, 44-2404-21) were coated overnight with recombinant PD-L1 (BPS, 71279) and diluted in carbonate-bicarbonate buffer (Sigma, C3041). Coated plates were blocked with 5% human serum albumin (BPL, PL08801 / 0007), followed by incubation with tested samples (serum or antibody standards) for capturing of anti-PD- L1 antibodies. Since the two anti-PD-L1 antibody variants have a different clearance rate, a distinct dilution scheme was used for each variant. Next, the plates were washed four times and incubated with purified mouse anti-human IgG Fc region secondary antibody (Thermo, 05-4500) for 1 hour, followed by four washes and incubation with peroxidase-conjugated goat anti-mouse polyclonal antibody (Jackson Immunoresearch, 115-035-003) for 30 minutes. Detection of bound anti-PD-L1 was done using TMB substrate (Southern biotech, 0410-01) according to the manufacturer’s instructions. Absorbance was recorded by using an ELISA plate reader at 450 nm with a 560 nm reference.

[0139] Assessment of embryonic versus maternal serum anti-PD-L1 levels revealed that serum analyzed from embryos taken from Group 1 dams showed significantly high levels of surr_null anti-PD-L1 antibodies (FIG. 1A), indicating that the surr_null variant possessed a native FcRn function. In contrast, serum analyzed from embryos taken from Group 2 dams showed significant low levels of surr_null-H310A anti-PD-L1 antibodies (FIG. 1 B), indicating that the surr_null-H310A variant has a significantly reduced capability to bind to FcRn. In addition, assessment of anti-PD- L1 antibody penetration into the placenta found that the surr_null variant exhibited 41 ±6% placental penetration (FIG. 2). In contrast, the surr_null-H310A variant showed only 0.46±0.09% placental penetration (FIG. 2). These results indicate that the surr_null-H310A variant showed significantly lower placental penetration compared to surr_null variant (41 ±6% vs 0.46±0.09%; embryonic / maternal serum). Taken together, these experiments demonstrate that an IgG antibody variant disclosed herein has reduced placental permeability and that such antibodies provide an enhanced safety profile in the treatment of a disease in a woman who is pregnant with a child or breast feeding an infant where such treatment may be harmful to the unborn baby or infant, as well as providing prophylactic care to a woman of childbearing age undergoing treatment for a disease where there is a possibility of conception.

[0140] In closing, foregoing descriptions of embodiments of the present invention have been presented for the purposes of illustration and description. It is to be understood that, although aspects of the present invention are highlighted by referring to specific embodiments, one skilledin the art will readily appreciate that these described embodiments are only illustrative of the principles comprising the present invention and such examples are not limiting thereto. As such, the specific embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0141] In addition, groupings of alternative embodiments, elements, steps and / or limitations of the present invention are not to be construed as limitations. Each such grouping may be referred to and claimed individually or in any combination with other groupings disclosed herein. It is anticipated that one or more alternative embodiments, elements, steps and / or limitations of a grouping may be included in, or deleted from, the grouping for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the grouping as modified, thus fulfilling the written description of all Markush groups used in the appended claims. In addition, all methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Therefore, it should be understood that embodiments of the disclosed subject matter are in no way limited to a particular element, compound, composition, component, article, apparatus, methodology, use, protocol, step, and / or limitation described herein, unless expressly stated as such.

[0142] While aspects of the invention have been described with reference to at least one exemplary embodiment, it is to be clearly understood by those skilled in the art that the invention is not limited thereto. Furthermore, those of ordinary skill in the art will recognize that certain changes, modifications, permutations, alterations, additions, subtractions, and sub-combinations thereof can be made in accordance with the teachings herein without departing from the spirit of the present invention. It is intended that the following appended claims and claims hereafter introduced are interpreted to include all such changes, modifications, permutations, alterations, additions, subtractions, and sub-combinations as are within their true spirit and scope. Accordingly, the scope of the present invention is not to be limited to that precisely as shown and described by this specification. Rather, the scope of the invention is to be interpreted only in conjunction with the appended claims and it is made clear, here, that the inventor(s) believe that the claimed subject matter is the invention.

[0143] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for conducting the invention. Of course, variations on thesedescribed embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0144] The words, language, and terminology used in this specification is for the purpose of describing particular embodiments, elements, steps and / or limitations only and is not intended to limit the scope of the present invention, which is defined solely by the claims. In addition, such words, language, and terminology are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus, if an element, step or limitation can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.

[0145] The definitions and meanings of the elements, steps or limitations recited in a claim set forth below are, therefore, defined in this specification to include not only the combination of elements, steps or limitations which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements, steps and / or limitations may be made for any one of the elements, steps or limitations in a claim set forth below or that a single element, step, or limitation may be substituted for two or more elements, steps and / or limitations in such a claim. Although elements, steps or limitations may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements, steps and / or limitations from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a sub-combination or variation of a subcombination. As such, notwithstanding the fact that the elements, steps and / or limitations of a claim are set forth below in a certain combination, it must be expressly understood that the invention includes other combinations of fewer, more, or different elements, steps and / or limitations, which are disclosed in above combination even when not initially claimed in such combinations. Furthermore, insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated asbeing equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements. Accordingly, the claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention.

[0146] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Similarly, as used herein, unless indicated to the contrary, the term “substantially” is a term of degree intended to indicate an approximation of the characteristic, item, quantity, parameter, property, or term so qualified, encompassing a range that can be understood and construed by those of ordinary skill in the art. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0147] Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints and open-ended ranges should be interpreted to include only commercially practical values. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.

[0148] Use of the terms “may” or “can” in reference to an embodiment or aspect of an embodiment also carries with it the alternative meaning of “may not” or “cannot.” As such, if the present specification discloses that an embodiment or an aspect of an embodiment may be orcan be included as part of the inventive subject matter, then the negative limitation or exclusionary proviso is also explicitly meant, meaning that an embodiment or an aspect of an embodiment may not be or cannot be included as part of the inventive subject matter. In a comparable manner, use of the term “optionally” in reference to an embodiment or aspect of an embodiment means that such embodiment or aspect of the embodiment may be included as part of the inventive subject matter or may not be included as part of the inventive subject matter. Whether such a negative limitation or exclusionary proviso applies will be based on whether the negative limitation or exclusionary proviso is recited in the claimed subject matter.

[0149] The terms “a,” “an,” “the” and similar references used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Further, ordinal indicators - such as, e.g., “first,” “second,” “third,” etc. - for identified elements are used to distinguish between the elements, and do not indicate or imply a required or limited number of such elements, and do not indicate a particular position or order of such elements unless otherwise specifically stated.

[0150] When used in the claims, whether as filed or added per amendment, the open-ended transitional term “comprising”, variations thereof such as, e.g., “comprise” and “comprises”, and equivalent open-ended transitional phrases thereof like “including”, “containing” and “having”, encompass all the expressly recited elements, limitations, steps, integers, and / or features alone or in combination with unrecited subject matter; the named elements, limitations, steps, integers, and / or features are essential, but other unnamed elements, limitations, steps, integers, and / or features may be added and still form a construct within the scope of the claim. Specific embodiments disclosed herein may be further limited in the claims using the closed-ended transitional phrases “consisting of’ or “consisting essentially of’ (or variations thereof such as, e.g., “consist of’, “consists of’, “consist essentially of’, and “consists essentially of’) in lieu of or as an amendment for “comprising.” When used in the claims, whether as filed or added per amendment, the closed-ended transitional phrase “consisting of’ excludes any element, limitation, step, integer, or feature not expressly recited in the claims. The closed-ended transitional phrase “consisting essentially of’ limits the scope of a claim to the expressly recited elements, limitations, steps, integers, and / or features and any other elements, limitations, steps, integers, and / or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. Thus, the meaning of the open-ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and / or features as well as any optional, additional unspecified ones. The meaning of the closed-ended transitional phrase “consisting of’ is being defined as only including those elements, limitations, steps,integers, and / or features specifically recited in the claim, whereas the meaning of the closed- ended transitional phrase “consisting essentially of” is being defined as only including those elements, limitations, steps, integers, and / or features specifically recited in the claim and those elements, limitations, steps, integers, and / or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. Therefore, the open-ended transitional phrase “comprising” (and equivalent open-ended transitional phrases thereof) includes within its meaning, as a limiting case, claimed subject matter specified by the closed-ended transitional phrases “consisting of’ or “consisting essentially of.” As such, the embodiments described herein or so claimed with the phrase “comprising” expressly and unambiguously provide description, enablement, and support for the phrases “consisting essentially of’ and “consisting of.”

[0151] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C .... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

[0152] Any claims intended to be treated under 35 U.S.C. §112(f) will begin with the words “means for,” but use of the term “for” in any other context is not intended to invoke treatment under 35 U.S.C. §112(f). Accordingly, Applicant reserves the right to pursue additional claims after filing this application, in either this application or in a continuing application.

[0153] It should be understood that the methods and the order in which the respective elements of each method are performed are purely exemplary. Depending on the implementation, they may be performed in any order or in parallel, unless indicated otherwise in the present disclosure.

[0154] Finally, all patents, patent publications, and other references cited and identified in the present specification are individually and expressly incorporated herein by reference in their entirety to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. These publications are provided solely for their disclosure prior to the filing date of the present application. The reference to any prior artin this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge from any country. In addition, where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. Lastly, nothing in this regard is or should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

CLAIMS1. A method of treating a disease in a pregnant subject in need thereof while minimizing one or more unwanted side effects to an unborn baby of the pregnant subject, the method comprising administering to the pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the unborn baby relative to the reference antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby, thereby protecting the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject.

2. The method according to claim 1 , wherein the IgG antibody variant is a human IgG antibody or a humanized IgG antibody.

3. The method according to claim 2, wherein the IgG antibody variant of the therapeutic antibody is IgG 1 , lgG2, lgG3, or lgG4.

4. The method according to claim 1 , wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

5. The method according to claim 4, wherein the one or more amino acid substitutions located in the Fc region further include one or more amino acid substitutions located at amino acidPCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn BabyDuring Immunotherapy residue positions L239, L240, I258, T261 , K293, H315, K327, S420, H438, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

6. The method according to claim 5, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, or H440, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

7. The method according to claim 6, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, and H440, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

8. The method according to claim 4, wherein the one or more amino acid substitutions located in the Fc region further include S303A / E338A / K339A, S244D / I337E, S244D / A335L / I337E,G241A, G241 A / S244D / I337E, G241A / A335L / I337E, G241A / S244D / A335L / I337E, F248L / R297P / Y305LA / 310I / P401 L, or L240V / F248L / R297P / Y305L / P401 L, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region is a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

9. The method according to claim 1 , wherein the therapeutic antibody is an anti-2B4 antibody, an anti- a4p7 integrin antibody, an anti-AXL antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H7 antibody, an anti-B7RP1 antibody, an anti-BAFF antibody, an anti- BAFFR antibody, an anti-BLyS antibody, anti-BTLA antibody, an anti-CCN2 antibody, an anti- CCR4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-C5 antibody, an anti-C19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD38 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD40L antibody, an anti-CD47 antibody, an anti- CD52 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD79p antibody, an anti-CD80 antibody, an anti-CD86 antibody, an anti-CD93 antibody, an anti-CD94 antibody, an anti-CD96 antibody, an anti-CD1 12 antibody, an anti-CD137 antibody, an anti-CD137L antibody, an anti-CD155 antibody, an anti-CD160 antibody, an anti-CD161 antibody, an anti-PCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn Baby During ImmunotherapyCD200 antibody, an anti-CD200R antibody, an anti-CD226 antibody, an anti-CGRP antibody, an anti-CGRPR antibody, an anti-CTLA-4 antibody, an anti-Dabigatran antibody, an anti- DNAM-1 antibody, an anti-EGFR antibody, an anti-EphA3R antibody, an anti-Factor IXa-X antibody, an anti-FGF23 antibody, an anti-FKN antibody, an anti-Galectin-9 antibody, an anti- GD2 antibody, an anti-GITR antibody, an anti-enterotoxin B (Clostridium difficile) antibody, an anti-GM-CSF antibody, an anti-GPIIb / llla antibody, an anti-HER2 antibody, an anti-HVEM antibody, an anti-ICOS antibody, an anti-ICOSL antibody, an anti-IDLR2 antibody, an anti-lgE antibody, an anti-IL-1 antibody, an anti-IL-4Ra antibody, an anti-IL-5 antibody, an anti-IL-5Ra antibody, an anti-IL-6 antibody, an anti-IL-6R antibody, an anti-IL-8 antibody, an anti-IL-13 antibody, an anti-IL-17a antibody, an anti-IL-17R antibody, an anti-IL-12 / 23 antibody, an anti- I L-23p19 antibody, an anti-ILT2 antibody, an anti-IFN-aR1 antibody, an anti-IFNy antibody, an anti-ITGA4 antibody, an anti-KIR antibody, an anti-KIR-L antibody, an anti-KIR2DL1 antibody, an anti-KIR2DL2 antibody, an anti-KIR2DL3 antibody, an anti-KIR3DL2 antibody, an anti- KLRG-1 antibody, an anti-LAG-3 antibody, an anti-LFA1 antibody, an anti-LIF antibody, an anti-LIR1 antibody, an anti-MAG antibody, an anti-MHC Class I molecule antibody, an anti- MHC Class II molecule antibody, an anti-NKG2A antibody, an anti-OX40 antibody, an anti- OX40L antibody, an anti-P-Selectin antibody, an anti-PA (B. anthrasis) antibody, an anti- PCSK9 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-PDGFRa antibody, an anti-Plasma Kallikrein antibody, an anti-PVRIG antibody, an anti- RANKL antibody, an anti-RSV antibody, an anti-Sclerostin antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec- 15 antibody, an anti-SIRPa antibody, an anti-SLAMF7 antibody, an anti-TIGIT antibody, an anti-TIM-3 antibody, an anti-TNFa antibody, an anti-TSLP antibody, an anti-VEGF antibody, an anti-VEGF-A antibody, an anti-VEGFR2 antibody, an anti- VISTA antibody, or an anti-von Willebrand factor antibody.

10. The method according to claim 1 , wherein the disease is an acute ischemic stroke, an asthma, an autoimmune disease, sepsis, a bacterial infection, a cancer, a diabetic nephropathy, an inflammatory disease, a psoriasis, a pulmonary fibrosis, a rheumatoid arthritis, a systemic lupus erythematosus, or a viral infection.1 1 . A method of treating a disease in a non-pregnant subject of childbearing age in need thereof, the method comprising administering to the non-pregnant subject a composition comprising an IgG antibody variant of a therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the referencePCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn Baby During Immunotherapy antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the breastfeeding baby relative to the reference antibody, wherein the non-pregnant subject of childbearing age is subject to a potential pregnancy of an unborn baby; and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant in the non-pregnant subject, thereby if the non-pregnant subject becomes pregnant, the method prophylactically protects the unborn baby at the time of conception from unwanted exposure to the IgG antibody variant while effectively treating the disease of the non-pregnant subject.

12. The method according to claim 11 , wherein the IgG antibody variant is a human IgG antibody or a humanized IgG antibody.

13. The method according to claim 12, wherein the IgG antibody variant of the therapeutic antibody is IgG 1 , lgG2, lgG3, or lgG4.

14. The method according to claim 11 , wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

15. The method according to claim 14, wherein the one or more amino acid substitutions are located in the Fc region further include one or more amino acid substitutions located at amino acid residue positions L239, L240, I258, T261 , K293, H315, K327, S420, H438, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

16. The method according to claim 15, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, or H440, or anyPCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn BabyDuring Immunotherapy combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

17. The method according to claim 16, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, and H440, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

18. The method according to claim 14, wherein the one or more amino acid substitutions located in the Fc region further include S303A / E338A / K339A, S244D / I337E, S244D / A335L / I337E,G241A, G241 A / S244D / I337E, G241 A / A335L / I337E, G241A / S244D / A335L / I337E, F248L / R297P / Y305L / V310I / P401 L, or L240V / F248L / R297P / Y305L / P401 L, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region is a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

19. The method according to claim 11 , wherein the therapeutic antibody is an anti-2B4 antibody, an anti- a4p7 integrin antibody, an anti-AXL antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H7 antibody, an anti-B7RP1 antibody, an anti-BAFF antibody, an anti- BAFFR antibody, an anti-BLyS antibody, anti-BTLA antibody, an anti-CCN2 antibody, an anti- CCR4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-C5 antibody, an anti-C19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD38 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD40L antibody, an anti-CD47 antibody, an anti- CD52 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD79p antibody, an anti-CD80 antibody, an anti-CD86 antibody, an anti-CD93 antibody, an anti-CD94 antibody, an anti-CD96 antibody, an anti-CD1 12 antibody, an anti-CD137 antibody, an anti-CD137L antibody, an anti-CD155 antibody, an anti-CD160 antibody, an anti-CD161 antibody, an anti- CD200 antibody, an anti-CD200R antibody, an anti-CD226 antibody, an anti-CGRP antibody, an anti-CGRPR antibody, an anti-CTLA-4 antibody, an anti-Dabigatran antibody, an anti- DNAM-1 antibody, an anti-EGFR antibody, an anti-EphA3R antibody, an anti-Factor IXa-X antibody, an anti-FGF23 antibody, an anti-FKN antibody, an anti-Galectin-9 antibody, an anti- GD2 antibody, an anti-GITR antibody, an anti-enterotoxin B (Clostridium difficile) antibody, an anti-GM-CSF antibody, an anti-GPIIb / llla antibody, an anti-HER2 antibody, an anti-HVEMPCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn Baby During Immunotherapy antibody, an anti-ICOS antibody, an anti-ICOSL antibody, an anti-IDLR2 antibody, an anti-lgE antibody, an anti-IL-1 antibody, an anti-IL-4Ra antibody, an anti-IL-5 antibody, an anti-IL-5Ra antibody, an anti-IL-6 antibody, an anti-IL-6R antibody, an anti-IL-8 antibody, an anti-IL-13 antibody, an anti-IL-17a antibody, an anti-IL-17R antibody, an anti-IL-12 / 23 antibody, an anti- I L-23p19 antibody, an anti-ILT2 antibody, an anti-IFN-aR1 antibody, an anti-IFNy antibody, an anti-ITGA4 antibody, an anti-KIR antibody, an anti-KIR-L antibody, an anti-KIR2DL1 antibody, an anti-KIR2DL2 antibody, an anti-KIR2DL3 antibody, an anti-KIR3DL2 antibody, an anti- KLRG-1 antibody, an anti-LAG-3 antibody, an anti-LFA1 antibody, an anti-LIF antibody, an anti-LIR1 antibody, an anti-MAG antibody, an anti-MHC Class I molecule antibody, an anti- MHC Class II molecule antibody, an anti-NKG2A antibody, an anti-OX40 antibody, an anti- OX40L antibody, an anti-P-Selectin antibody, an anti-PA (S. anthrasis) antibody, an anti- PCSK9 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-PDGFRa antibody, an anti-Plasma Kallikrein antibody, an anti-PVRIG antibody, an anti- RANKL antibody, an anti-RSV antibody, an anti-Sclerostin antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec-15 antibody, an anti-SIRPa antibody, an anti-SLAMF7 antibody, an anti-TIGIT antibody, an anti-TIM-3 antibody, an anti-TNFa antibody, an anti-TSLP antibody, an anti-VEGF antibody, an anti-VEGF-A antibody, an anti-VEGFR2 antibody, an anti-VISTA antibody, or an anti-von Willebrand factor antibody.

20. The method according to claim 11 , wherein the disease is an acute ischemic stroke, an asthma, an autoimmune disease, sepsis, a bacterial infection, a cancer, a diabetic nephropathy, an inflammatory disease, a psoriasis, a pulmonary fibrosis, a rheumatoid arthritis, a systemic lupus erythematosus, or a viral infection.

21. A method of preventing or minimizing FcRn-dependent active transport of a therapeutic antibody from a pregnant subject to an unborn baby of the pregnant subject, the method comprising administering to the pregnant subject a composition comprising an IgG antibody variant of the therapeutic antibody, wherein the IgG antibody variant of the therapeutic antibody includes a heavy chain having one or more amino acid substitutions in a Fc region that reduces binding affinity of the IgG antibody variant to a neonatal Fc receptor relative to a reference antibody, the reference antibody being the therapeutic antibody that lacks the one or more amino acid modifications but otherwise has the same amino acid sequence as the IgG antibody variant, wherein the IgG antibody variant of the therapeutic antibody reduces the one or more unwanted side effects to the unborn baby relative to the reference antibody,PCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn Baby During Immunotherapy wherein the pregnant subject is afflicted with a disease that is treatable with the IgG antibody variant of the therapeutic antibody, and wherein the method reduces an FcRn-dependent active transport of the IgG antibody variant from the pregnant subject to the unborn baby, thereby protecting the unborn baby from unwanted exposure to the IgG antibody variant while effectively treating the disease of the pregnant subject.

22. The method according to claim 21 , wherein the IgG antibody variant is a human IgG antibody or a humanized IgG antibody.

23. The method according to claim 22, wherein the IgG antibody variant of the therapeutic antibody is IgG 1 , lgG2, lgG3, or lgG4.

24. The method according to claim 21 , wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, G241 , S244, F248, K253, T255, M257, I258, S259, R260, T261 , P262, H273, D275, E277, H290, K293, K295, P296, R297, S303, Y305, V310, V313, L314, H315, Q316, L319, K327, K331 , A335, I337, E338, K339, D361 , E362, L363, P401 , S420, M433, H438, N439, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

25. The method according to claim 24, wherein the one or more amino acid substitutions located in the Fc region further include one or more amino acid substitutions located at amino acid residue positions L239, L240, I258, T261 , K293, H315, K327, S420, H438, H440, or Y441 , or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

26. The method according to claim 25, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, or H440, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

27. The method according to claim 26, wherein the one or more amino acid substitutions located in the Fc region are at amino acid residue positions L239, L240, H315, K327, and H440, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.PCT Patent Application UEIBC1-0017WOKertser, et al., Methods for Reducing IgG Antibody Transfer from Mother to Unborn BabyDuring Immunotherapy28. The method according to claim 24, wherein the one or more amino acid substitutions located in the Fc region further include S303A / E338A / K339A, S244D / I337E, S244D / A335L / I337E,G241A, G241 A / S244D / I337E, G241 A / A335L / I337E, G241A / S244D / A335L / I337E, F248L / R297P / Y305LA / 310I / P401 L, or L240V / F248L / R297P / Y305L / P401 L, or any combination thereof, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1 ; or wherein the one or more amino acid substitutions located in the Fc region is a combination of L234Y / L235Q / G236W / S239M / H268D / D270E / S298A on one heavy chain and D270E / K326D / A330M / K334E on an opposing heavy chain, the amino acid residue positions based on IgG heavy chain sequence SEQ ID NO: 1.

29. The method according to claim 21 , wherein the therapeutic antibody is an anti-2B4 antibody, an anti- a4p7 integrin antibody, an anti-AXL antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H7 antibody, an anti-B7RP1 antibody, an anti-BAFF antibody, an anti- BAFFR antibody, an anti-BLyS antibody, anti-BTI_A antibody, an anti-CCN2 antibody, an anti- CCR4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-C5 antibody, an anti-C19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD38 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD40L antibody, an anti-CD47 antibody, an anti- CD52 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD79p antibody, an anti-CD80 antibody, an anti-CD86 antibody, an anti-CD93 antibody, an anti-CD94 antibody, an anti-CD96 antibody, an anti-CD1 12 antibody, an anti-CD137 antibody, an anti-CD137L antibody, an anti-CD155 antibody, an anti-CD160 antibody, an anti-CD161 antibody, an anti- CD200 antibody, an anti-CD200R antibody, an anti-CD226 antibody, an anti-CGRP antibody, an anti-CGRPR antibody, an anti-CTLA-4 antibody, an anti-Dabigatran antibody, an anti- DNAM-1 antibody, an anti-EGFR antibody, an anti-EphA3R antibody, an anti-Factor IXa-X antibody, an anti-FGF23 antibody, an anti-FKN antibody, an anti-Galectin-9 antibody, an anti- GD2 antibody, an anti-GITR antibody, an anti-enterotoxin B (Clostridium difficile) antibody, an anti-GM-CSF antibody, an anti-GPIIb / llla antibody, an anti-HER2 antibody, an anti-HVEM antibody, an anti-ICOS antibody, an anti-ICOSL antibody, an anti-IDLR2 antibody, an anti-lgE antibody, an anti-IL-1 p antibody, an anti-IL-4Ra antibody, an anti-IL-5 antibody, an anti-IL-5Ra antibody, an anti-IL-6 antibody, an anti-IL-6R antibody, an anti-IL-8 antibody, an anti-IL-13 antibody, an anti-IL-17a antibody, an anti-IL-17R antibody, an anti-IL-12 / 23 antibody, an anti- I L-23p19 antibody, an anti-ILT2 antibody, an anti-IFN-aR1 antibody, an anti-IFNy antibody, an anti-ITGA4 antibody, an anti-KIR antibody, an anti-KIR-L antibody, an anti-KIR2DL1 antibody,an anti-KIR2DL2 antibody, an anti-KIR2DL3 antibody, an anti-KIR3DL2 antibody, an anti- KLRG-1 antibody, an anti-LAG-3 antibody, an anti-LFA1 antibody, an anti-LIF antibody, an anti-LIR1 antibody, an anti-MAG antibody, an anti-MHC Class I molecule antibody, an anti- MHC Class II molecule antibody, an anti-NKG2A antibody, an anti-OX40 antibody, an anti- OX40L antibody, an anti-P-Selectin antibody, an anti-PA (8. anthrasis) antibody, an anti- PCSK9 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-PDGFRa antibody, an anti-Plasma Kallikrein antibody, an anti-PVRIG antibody, an anti- RANKL antibody, an anti-RSV antibody, an anti-Sclerostin antibody, an anti-Siglec-7 antibody, an anti-Sig lec-9 antibody, an anti-Siglec-15 antibody, an anti-SIRPa antibody, an anti-SLAMF7 antibody, an anti-TIGIT antibody, an anti-TIM-3 antibody, an anti-TNFa antibody, an anti-TSLP antibody, an anti-VEGF antibody, an anti-VEGF-A antibody, an anti-VEGFR2 antibody, an anti- VISTA antibody, or an anti-von Willebrand factor antibody.

30. The method according to claim 21 , wherein the disease is an acute ischemic stroke, an asthma, an autoimmune disease, sepsis, a bacterial infection, a cancer, a diabetic nephropathy, an inflammatory disease, a psoriasis, a pulmonary fibrosis, a rheumatoid arthritis, a systemic lupus erythematosus, or a viral infection.

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