Intravenous (IV) infusion remains the predominant delivery route for oncology monoclonal antibodies, but it requires prolonged chair time and substantial infusion-unit resources. Hyaluronidase-facilitated subcutaneous (SC) formulations aim to shorten administration (minutes vs hours), improve convenience, and potentially expand outpatient or home-based delivery, while preserving exposure, efficacy, and safety. We conducted a narrative review of published clinical studies, major congress presentations, trial registries, and Food and Drug Administration (FDA)/European Medicines Agency (EMA) regulatory documents describing development of hyaluronidase-facilitated SC formulations for seven oncology antibodies (trastuzumab, rituximab, daratumumab, atezolizumab, nivolumab, pembrolizumab, and amivantamab). We extracted evidence on formulation strategy, pharmacokinetic (PK) bridging, efficacy comparability, safety/immunogenicity, and regulatory pathways supporting IV→SC approval. Across programs, PH20-based recombinant hyaluronidases, including human hyaluronidase PH20 (rHuPH20) and berahyaluronidase alfa, transiently depolymerize SC hyaluronan, enabling delivery of multi-milliliter injections and high fixed doses. Development strategies converged on PK-anchored bridging, typically targeting non-inferior SC/IV geometric-mean ratios for both initiation and maintenance exposure (e.g., cycle-1 area under the curve [AUC]/average plasma concentration [Cavg] and minimum plasma concentration [Cmin]/trough concentration [Ctrough]), supported by population PK to ensure covariate coverage. We highlight a pragmatic evolution in trial design: earlier conversions often paired PK with direct clinical activity confirmation in sensitive settings, whereas more recent programs increasingly use prespecified PK non-inferiority as the confirmatory backbone with efficacy as supportive reassurance—enabling use of an approved SC formulation across multiple indications. In pivotal bridging trials, SC regimens generally met or exceeded exposure targets and demonstrated efficacy consistent with IV comparators (treatment effects clustering around unity; Δ ≈ 0; hazard ratio/relative risk ≈ 1). Safety profiles were broadly similar; SC administration was associated with fewer administration-related reactions for several agents, while injection-site reactions were usually mild. Immunogenicity, including anti-hyaluronidase antibodies, did not show consistent clinically meaningful effects on PK or outcomes. Hyaluronidase-facilitated IV→SC conversion has become a reproducible, model-informed, PK-driven development paradigm. By synthesizing study-design choices, formulation pathways, and extrapolation logic across seven approved antibodies—including the recent IO and targeted-therapy wave—this review builds upon a previously described clinical bridging concept and provides a comprehensive updated overview including the most recently approved products, with a practical framework to guide future IV→SC transitions in oncology.

Transitioning Therapeutic Antibodies in Oncology from Intravenous to Hyaluronidase-Facilitated Subcutaneous Administration

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发表日期：

2026年7月16日

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Xu Steven Xu

摘要

Intravenous (IV) infusion remains the predominant delivery route for oncology monoclonal antibodies, but it requires prolonged chair time and substantial infusion-unit resources. Hyaluronidase-facilitated subcutaneous (SC) formulations aim to shorten administration (minutes vs hours), improve convenience, and potentially expand outpatient or home-based delivery, while preserving exposure, efficacy, and safety. We conducted a narrative review of published clinical studies, major congress presentations, trial registries, and Food and Drug Administration (FDA)/European Medicines Agency (EMA) regulatory documents describing development of hyaluronidase-facilitated SC formulations for seven oncology antibodies (trastuzumab, rituximab, daratumumab, atezolizumab, nivolumab, pembrolizumab, and amivantamab). We extracted evidence on formulation strategy, pharmacokinetic (PK) bridging, efficacy comparability, safety/immunogenicity, and regulatory pathways supporting IV→SC approval. Across programs, PH20-based recombinant hyaluronidases, including human hyaluronidase PH20 (rHuPH20) and berahyaluronidase alfa, transiently depolymerize SC hyaluronan, enabling delivery of multi-milliliter injections and high fixed doses. Development strategies converged on PK-anchored bridging, typically targeting non-inferior SC/IV geometric-mean ratios for both initiation and maintenance exposure (e.g., cycle-1 area under the curve [AUC]/average plasma concentration [C_avg] and minimum plasma concentration [C_min]/trough concentration [C_trough]), supported by population PK to ensure covariate coverage. We highlight a pragmatic evolution in trial design: earlier conversions often paired PK with direct clinical activity confirmation in sensitive settings, whereas more recent programs increasingly use prespecified PK non-inferiority as the confirmatory backbone with efficacy as supportive reassurance—enabling use of an approved SC formulation across multiple indications. In pivotal bridging trials, SC regimens generally met or exceeded exposure targets and demonstrated efficacy consistent with IV comparators (treatment effects clustering around unity; Δ ≈ 0; hazard ratio/relative risk ≈ 1). Safety profiles were broadly similar; SC administration was associated with fewer administration-related reactions for several agents, while injection-site reactions were usually mild. Immunogenicity, including anti-hyaluronidase antibodies, did not show consistent clinically meaningful effects on PK or outcomes. Hyaluronidase-facilitated IV→SC conversion has become a reproducible, model-informed, PK-driven development paradigm. By synthesizing study-design choices, formulation pathways, and extrapolation logic across seven approved antibodies—including the recent IO and targeted-therapy wave—this review builds upon a previously described clinical bridging concept and provides a comprehensive updated overview including the most recently approved products, with a practical framework to guide future IV→SC transitions in oncology.