Receptor Occupancy data to predict the minimum effective dose

 Use RO data to predict the minimum effective dose and the biologically optimal dose for a PD-1–targeting monoclonal antibody in humans.

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🔬 Step 1: Known Parameters

Parameter	Value
Target	PD-1 (on activated T cells)
Affinity (KD)	3 nM (i.e., 3 × 10⁻⁹ M)
MAb MW	150 kDa
Desired RO for efficacy	≥70%
Plasma volume	3 L (approximate)
Bioavailability (IV)	100%
RO vs. plasma concentration	Modeled by: RO = C / (C + KD)

🧮 Step 2: Determine Required Plasma Concentration for Desired RO

Use the RO equation:

$$RO = \frac{[Drug]}{[Drug] + K_D}$$

For 70% RO:

$$0.7 = \frac{C}{C + 3 \times 10^{-9}} \Rightarrow C = 7 \times 10^{-9}\ M$$

Convert to µg/mL:

$$C = 7 \times 10^{-9}\ mol/L \times 150,000\ g/mol = 1.05\ \mu g/mL$$

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🧮 Step 3: Estimate Dose

To achieve 1.05 µg/mL in 3 L plasma:

$$1.05\ \mu g/mL \times 3000\ mL = 3150\ \mu g = 3.15\ mg$$

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So:

• A 3–5 mg IV dose would achieve ~70% PD-1 occupancy, assuming full distribution in plasma.

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🔁 Step 4: Evaluate Higher RO Targets

RO (%)	Required [Drug]	Estimated Total Dose
10%	0.33 nM	~0.15 mg
50%	3.0 nM	~1.35 mg
70%	7.0 nM	~3.15 mg
90%	27 nM	~12.15 mg

Saturation begins above 90% RO (~10–20 mg)

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📈 Dose–RO Graph

Would look like this (sigmoidal):

RO (%)
 │                                •
 │                            •  
 │                        •
 │                    •
 │                •
 │            •
 │        •
 │    •
 └─────────────────────────────▶ Dose (mg)
     0   1   3   5   10   20

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✅ Clinical Correlation (Nivolumab Example)

• 0.1 mg/kg → Low plasma conc., ~10–20% RO → Minimal effect

• 1.0 mg/kg → ~60–70% RO → Biological activity begins

• 3.0 mg/kg → ~90% RO → Clinical responses observed

• 10 mg/kg → >95% RO → No additional benefit vs. 3 mg/kg

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📊 Summary

Dose	RO (%)	Clinical Relevance
<1 mg	<50%	Below effective threshold
1–3 mg	70–90%	Optimal PD effect
>10 mg	>95%	Saturation (no added benefit)