A Multicenter, Randomized, Open-Label Trial Comparing the Efficacy and Safety of Monoclonal Anti-Rh (D) Immunoglobulin with Polyclonal Anti-Rh (D) Immunoglobulin for the Prevention of Maternal Rh-Isoimmunization

Chauhan, Anahita; Nandanwar, Y. S.; Ramaiah, Aruna; Yelikar, Kanan; Rashmi, M D; Sachan, Rekha; Mayekar, Rahul; Trivedi, Yamini; Paradkar, Gopalkrishna; Patole, Kiran

doi:10.1007/s13224-019-01234-2

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…Additionally, there was discordance between RhD + RBC clearance and immunoprophylaxis among the anti-D monoclonal antibodies evaluated ( 8 ), challenging the explanation that anti-D works by clearing RhD + RBCs. Recently, two new monoclonal anti-D antibodies demonstrated efficacy in preventing RhD alloimmunization in pregnant women ( 10 , 11 ), although additional studies with a larger number of participants and re-exposure to RhD+ RBCs are required to fully evaluate the efficacy of these new therapeutics.…”

Section: Introductionmentioning

confidence: 99%

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

et al. 2022

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Passive immunization with anti-D can prevent maternal alloimmunization to RhD thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, anti-D fails in some cases and some monoclonal anti-D preparations paradoxically enhances alloimmunization. The underlying mechanisms modulating humoral alloimmunization by anti-D are unknown. We previously reported that IgG antibody subclasses differentially regulate alloimmunity in response to red blood cell (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC immune complexes were preferentially consumed by the splenic dendritic cell (DC) subsets that play a role in RBC alloimmunization. The deletion of activating Fc-gamma receptors (FcγRs) (i.e., FcγRI, FcγRIII, and FcγRIV) on DCs abrogated IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of FcγRIV, which has high affinity for the IgG2c subclass, we hypothesized that FcγRIV was required for enhanced alloimmunization. To test this hypothesis, knockout mice and blocking antibodies were used to manipulate FcγR expression. The data presented herein demonstrate that FcγRIV, but not FcγRI or FcγRIII, is required for IgG2c-mediated enhancement of RBC alloantibody production. Additionally, FcγRI is alone sufficient for IgG2c-mediated RBC clearance but not for increased alloimmunization, demonstrating that RBC clearance can occur without inducing alloimmunization. Together, these data, combined with prior observations, support the hypothesis that passive immunization with an RBC-specific IgG2c antibody increases RBC alloantibody production through FcγRIV ligation on splenic conventional DCs (cDCs). This raises the question of whether standardizing antibody subclasses in immunoprophylaxis preparations is desirable and suggests which subclasses may be optimal for generating monoclonal anti-D therapeutics.

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Section: Introductionmentioning

confidence: 99%

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

et al. 2022

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“…Moreover, under certain circumstances, anti-D results in enhancement, rather than suppression, of alloimmunization to RhD (3). Finally, attempts to generate a monoclonal anti-D have largely failed, resulting in either decreased efficacy compared to donor derived anti-D, or in some cases, monoclonal anti-D has shown the same paradoxical enhancement of alloimmunization seen with certain preparations of donor derived anti-D (4,5); although a recent report indicates great progress in this area (6). Why anti-D suppresses alloimmunization in some cases and enhances alloimmunization in others remains an unsolved question.…”

Section: Introductionmentioning

confidence: 99%

IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice

et al. 2020

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It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.

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“…Varying efficacies have been reported across products concerning the clearance rate of Rhpositive RBCs from blood circulation. [22][23][24][25] Chauhan et al 15 reported similarities between Rhoclone ® , a monoclonal anti-D antibody product (Bharat Serums and Vaccines Ltd., India), and its poly-anti-D counterpart with reference to clinical effects in a large number of women requiring anti-D in the clinical setting. It is noteworthy that in all studies, the safety profiles for both mono-and R-anti-D immunoglobulins have been consistent and comparable with that of poly-anti-D. 14,26 AntiD is a recombinant anti-D product that has been approved for use as an anti-D prophylaxis treatment in Rh-negative women carrying an Rh-positive fetus and who had experienced a sensitizing event during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…14 Monoclonal anti-D immunoglobulins (mono-anti-D), manufactured using the hybridoma technique, were introduced to mitigate these problems. 11,13,15 However, the maintenance of hybridoma cultures and the generation of monoclonal antibodies is a time-consuming and laborious process. Moreover, the limited availability of hybridoma growth supplements such as fetal bovine serum is a major obstacle to the adequate production of monoanti-D. 16,17 The development of recombination anti-D immunoglobulins (R-anti-D) has provided a viable option to overcome the obstacles associated with mono-anti-D.…”

Section: Introductionmentioning

confidence: 99%

Post-marketing safety evaluation of recombinant anti-rho (D) immunoglobulin for the prevention of maternal rh-isoimmunization: A prospective, multi-centre, phase IV study

Shah,

Saigal,

Naik

et al. 2023

IJOGR

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AntiD is a recombinant anti-D immunoglobulin approved as an immunoprophylaxis treatment in Rh-negative mothers carrying an Rh-positive fetus. This study was conducted to assess the safety and tolerability of AntiD in clinical settings. This was a prospective, multicenter, phase IV, post-marketing safety study of AntiD. The study was conducted at 29 hospitals in India as per regulatory requirements. Three hundred eligible Rh-negative women were administered a single intramuscular dose of either 150 mcg or 300 mcg AntiD within 72 hours of a sensitizing event as per the approved indication. Safety and tolerability were evaluated based on the assessment of adverse events (AEs) and serious adverse events (SAEs) reported during the study.Out of the 300 participants enrolled, 290 completed the study procedures. A total of 54 AEs and 34 treatment-emergent adverse events (TEAEs) were reported by 47 (15.7%) and 30 (10.0%) participants, respectively. Most reported TEAEs were mild, unrelated to the study drug, and were completely resolved during the study. Except for two participants with clinically significant hematological and urinalysis findings consistent with their underlying medical conditions, none of the participants exhibited abnormal clinical or laboratory parameters. Based on the assessment of the different safety parameters, AntiD administered at a dose of either 150 mcg or 300 mcg did not raise any new or significant safety concerns. The current study demonstrated that AntiD is well-tolerated and safe to use for anti-D prophylaxis as per product label indications for the prevention of Rh-isoimmunization in a clinical setting.

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A Multicenter, Randomized, Open-Label Trial Comparing the Efficacy and Safety of Monoclonal Anti-Rh (D) Immunoglobulin with Polyclonal Anti-Rh (D) Immunoglobulin for the Prevention of Maternal Rh-Isoimmunization

Cited by 7 publications

References 14 publications

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice

Post-marketing safety evaluation of recombinant anti-rho (D) immunoglobulin for the prevention of maternal rh-isoimmunization: A prospective, multi-centre, phase IV study

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